Novel lxr modulators with bicyclic core moiety

ABSTRACT

The present invention relates to bicyclic compounds (e.g. indoles) containing a sulfonyl moiety, which bind to the liver X receptor (LXRα and/or LXKβ) and act preferably as inverse agonists of LXR.

The present invention relates to novel compounds which are Liver XReceptor (LXR) modulators and to pharmaceutical compositions containingsame. The present invention further relates to the use of said compoundsin the prophylaxis and/or treatment of diseases which are associatedwith the modulation of the Liver X Receptor.

BACKGROUND

The Liver X Receptors, LXRα (NR1H3) and LXRβ (NR1H2) are members of thenuclear receptor protein superfamily. Both receptors form heterodimericcomplexes with Retinoid X Receptor (RXRα, β or γ) and bind to LXRresponse elements (e.g. DR4-type elements) located in the promoterregions of LXR responsive genes. Both receptors are transcriptionfactors that are physiologically regulated by binding ligands such asoxysterols or intermediates of the cholesterol biosynthetic pathwayssuch as desmosterol. In the absence of a ligand, the LXR-RXR heterodimeris believed to remain bound to the DR4-type element in complex withco-repressors, such as NCOR1, resulting in repression of thecorresponding target genes. Upon binding of an agonist ligand, either anendogenous one such as the oxysterols or steroid intermediates mentionedbefore or a synthetic, pharmacological ligand, the conformation of theheterodimeric complex is changed, leading to the release of corepressorproteins and to the recruitment of coactivator proteins such as NCOA1(SRC1), resulting in transcriptional stimulation of the respectivetarget genes. While LXRP is expressed in most tissues, LXRα is expressedmore selectively in cells of the liver, the intestine, adipose tissueand macrophages. The relative expression of LXRα and LXRβ at the mRNA orthe protein level may vary between different tissues in the same speciesor between different species in a given tissue. The LXR's controlreverse cholesterol transport, i.e. the mobilization of tissue-boundperipheral cholesterol into HDL and from there into bile and feces,through the transcriptional control of target genes such as ABCA1 andABCG1 in macrophages and ABCG5 and ABCG8 in liver and intestine. Thisexplains the anti-atherogenic activity of LXR agonists in dietaryLDLR-KO mouse models. The LXRs, however, do also control thetranscription of genes involved in lipogenesis (e.g. Srebp1c, Scd1,Fasn) which accounts for the liver steatosis observed followingprolonged treatment with LXR agonists.

The liver steatosis liability is considered a main barrier for thedevelopment of non-selective LXR agonists for atherosclerosis treatment.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a manifestationof metabolic syndrome in the liver and NAFLD has reached epidemicprevalences worldwide (Estes et al., Hepatology 2018; 67:123; Estes etal., J. Hepatol. 2018; 69:896). The pathologies of NAFLD range frombenign and reversible steatosis to steatohepatitis (nonalcoholicsteatohepatitis, NASH) that can develop towards fibrosis, cirrhosis andpotentially further towards hepatocellular carcinogenesis. Classically,a two-step model has been employed to describe the progression of NAFLDinto NASH, with hepatic steatosis as an initiating first stepsensitizing towards secondary signals (exogenous or endogenous) thatlead to inflammation and hepatic damage (Day et al., Gastroenterology1998; 114:842). Nowadays, the transition from benign NAFLD towards themore aggressive state NASH is regarded as multifactorial with genetic,environmental, lifestyle and nutritional influences playing differentroles in different individual setups. Independent from the etiology ofthe disease there is a very strong unmet medical need to stopprogression of NAFLD because of the detrimental sequelae such as livercirrhosis, hepatocellular carcinoma or other forms of liver relatedmodalities.

LXR expression levels are firmly associated with the state of NAFLD.Notably, LXR expression was shown to correlate with the degree of fatdeposition, as well as with hepatic inflammation and fibrosis in NAFLDpatients (Ahn et al., Dig. Dis. Sci. 2014; 59:2975). Furthermore, serumand liver desmosterol levels are increased in patients with NASH but notin people with simple liver steatosis. Desmosterol has beencharacterized as a potent endogenous LXR agonist (Yang et al., J. Biol.Chem. 2006; 281:27816). Given the known involvement of the LXRs asmaster regulators of hepatic lipidogenesis and lipid metabolism, ingeneral and the aforementioned association of LXR expression levels withthe stage of fatty liver disease, NAFLD/NASH patients might thereforebenefit from blocking the increased LXR activity in the livers of thesepatients through small molecule antagonists or inverse agonists thatshut off LXRs' activity. While doing so it needs to be taken care thatsuch LXR antagonists or inverse agonists do not interfere with LXRs inperipheral tissues or macrophages to avoid disruption of theanti-atherosclerotic reverse cholesterol transport governed by LXR inthese tissues or cells.

Certain publications (e.g. Peet et al., Cell 1998; 93:693 and Schultz etal., Genes Dev. 2000; 14:2831) have highlighted the role of LXRα, inparticular, for the stimulation of lipidogenesis and hence establishmentof NAFLD in the liver. They indicate that it is mainly LXRα beingresponsible for the hepatic steatosis, hence an LXRα-specific antagonistor inverse agonist might suffice or be desirable to treat just hepaticsteatosis. These data, however, were generated only by comparing LXRα,LXRs or double knockout with wild-type mice with regards to theirsusceptibility to develop steatosis on a high fat diet. They do notaccount for a major difference in the relative expression levels of LXRαand LXRβ in the human as opposed to the murine liver. Whereas LXRα isthe predominant LXR subtype in the rodent liver, LXRβ is expressed toabout the same if not higher levels in the human liver compared to LXRα(data from Unigene or other expression databases). This was exemplifiedby testing an LXRP selective agonist in human phase I clinical studies(Kirchgessner et al., Cell Metab. 2016; 24:223) which resulted in theinduction of strong hepatic steatosis although it was shown to notactivate human LXRα.

Hence it can be assumed that it should be desirable to have no strongpreference of an LXR modulator designed to treat NAFLD or NASH for aparticular LXR subtype. A certain degree of LXR-subtype selectivitymight be allowed if the pharmacokinetic profile of such a compoundclearly ensures sufficient liver exposure and resident time to coverboth LXRs in clinical use.

In summary, the treatment of diseases such as NAFLD or NASH would needLXR modulators that block LXRs in a hepato-selective fashion and thiscould be achieved through hepatotropic pharmacokinetic and tissuedistribution properties that have to be built into such LXR modulators.

The master control on lipidogenesis is exerted by LXRs in all major celltypes studied so far. Cancer cells are also highly dependent on de novolipidogenesis and therefore Flaveny et al. tested the LXR inverseagonist tool compound SR9243 in cancer cells and in animal cancer models(Cancer Cell 2015; 28:42). They could show that SR9243 inhibitedlipidogenesis along with the Warburg glycolysis effect, in general, andthat this molecular effect led to apoptosis and diminished tumor growthin vivo.

PRIOR ART

Zuercher et al. describes with the structurally unrelated tertiarysulfonamide GSK2033 the first potent, cell-active LXR antagonists (J.Med. Chem. 2010; 53:3412). Later, this compound was reported to displaya significant degree of promiscuity, targeting a number of other nuclearreceptors (Griffett & Burris, Biochem. Biophys. Res. Commun. 2016;479:424). It is stated, that GSK2033 showed rapid clearance(Cl_(int)>1.0 mL/min/mg protein) in rat and human liver microsomalassays and that this rapid hepatic metabolism of GSK2033 precludes itsuse in vivo. As such GSK2033 is a useful chemical probe for LXR incellular studies only.

WO2014/085453 describes the preparation of structurally unrelated smallmolecule LXR inverse agonists of Formula (A) in addition to structureGSK2033 above:

The following compounds from this application, in particular, arefurther described in some publications, mainly from the same group ofinventors/authors: SR9238 is described as a liver-selective LXR inverseagonist that suppresses hepatic steatosis upon parenteral administration(Griffett et al., ACS Chem. Biol. 2013; 8:559). After estersaponification of SR9238 the LXR inactive acid derivative SR10389 isformed. This compound then has systemic exposure. In addition, it wasdescribed, that SR9238 suppresses fibrosis in a model of NASH againafter parenteral administration (Griffett et al., Mol. Metab. 2015;4:35). With related SR9243 the effects on aerobic glycolysis (Warburgeffect) and lipogenesis were described (Flaveny et al., Cancer Cell2015; 28:42) and the NASH-suppressing data obtained with SR9238 wasconfirmed by Huang et al. (BioMed Res. Int. 2018; 8071093) using SR9243.

WO2003/082802 describes structurally unrelated LXR agonists of generalFormula (B):

In all examples the acid containing (hetero)aryl moiety is linked via anoxygen atom to the rest of the molecule. Most interesting examples areGW3965 (Collins et al. J. Med. Chem. 2002; 45:1963) and clinicalcandidate RGX-104 from Rgenix.

Yu et al. (J. Org. Chem. 2018; 83:323) describes the synthesis of2,3-disubstituted indoles via the following reaction scheme. The onlyexample with an ortho-substituted aryl in 3-position of the indole isstructure C1.

WO2016/207217 discloses bicyclic derivatives of Formula (D), which doesnot fall within the scope of the present invention, since no —SO₂-linkedresidue is possible for A, which may represent a bicyclic structureincluding indole. However intermediate D1 is disclosed (Example 69, StepE), which is the only example with an ortho-substituted aryl in3-position of the indole.

WO2016/106266 discloses azaindoles of Formula E as TGFβ antagonists

wherein R is an optionally substituted heterocyclic or heterobicyclicgroup, R⁸ is selected from a broad range of substituents including—SO₂R⁹. Residue R⁹ can be selected from a broad range of substituentsincluding C₃-C₆-cycloalkyl and heterocycloalkyl. The only exampleswherein both the 2- and 3-position of the azaindole is substituted witha cyclic moiety is structure E1 and E2.

WO2013/111150 discloses adamantane derivatives of Formula (F) as17β-hydroxysteroid dehydrogenase type 1 inhibitors

wherein Ar is an optionally substituted C₁-C₁₈-heteroaryl group, A canbe —SO₂— and B can be absent. No examples are shown, which fall withinthe scope of the present invention.

WO2013/028999 discloses structures of Formula (G) as potentialtherapeutics for neuropsychiatric disorders

wherein Z may be absent and A represents a ring structure, e.g.3-substituted indole of Formula (G1). Here R¹⁵ and R¹⁷ can be selectedfrom an optionally substituted aryl and heteroaryl moiety. However forthis case, no examples are shown.

WO2013/012649 discloses azaindoles of Formula (H) for the treatment ofHIV

wherein linker element L can be —SO₂—, R⁵ and R⁶ can independently beselected from a broad range of substituents including an optionallysubstituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In mostcases, R² is a carboxylic acid or bioisostere thereof. No examples areshown, which fall within the scope of the present invention.

WO2010/124793 and WO2008/132434 disclose azaindoles of Formula (J) asfungicides

wherein R⁴ can be selected from a broad range of substituents includingan optionally substituted cyclyl, heterocyclyl, aryl and heteroaryl. R³can be selected from a broad range of substituents including —SO₂R¹²,with R¹² again can be selected from abroad range of substituentsincluding an optionally substituted cyclyl, heterocyclyl, aryl andheteroaryl. The only example wherein both the 2- and 3-position of theazaindole is substituted with a cyclic moiety is structure J1.

WO2010/010186 discloses JAK kinase inhibitors of Formula (K)

wherein ring Cy is selected from aryl and heteroaryl. With L¹ equalsSO₂, n equals 0, R^(3a) e.g. unsubstituted cycloalkyl, heterocycloalkyl,aryl or heteroaryl and R^(3b) selected from optionally substitutedcycloalkyl, heterocycloalkyl, aryl or heteroaryl derivatives falling inthe scope of the present invention can be constructed, however noexamples are shown.

WO2009/032116 discloses indoles of Formula (L) for treating viralinfections

wherein R¹ can be selected from a broad range of substituents including—SO₂—. For R² the cyclic moieties (L1 to L3) and for R³ the cyclicmoieties (L4 and L5) are possible. In related application WO2009/032125and WO2009/064848 even more cyclic moieties for R³ are possible. R¹⁰ canbe selected from optionally substituted cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. InWO2009/064852, a cyclic moiety of structure L6 is possible for R³. Inall applications, no examples are shown, which fall within the scope ofthe present invention.

WO2008/116833 discloses azetidine compounds of Formula (M) for treatingdisorders that respond to modulation of the serotonin5-hydroxytryptamine-6 (5-HT₆) receptor

wherein X¹ and X² are independently N or CR^(x). Residue R^(x) can beselected from a broad range of substituents including an optionallysubstituted phenyl or C₃₋₆-cycloalkyl. Residue A can be selected fromoptionally substituted C₃₋₆-cycloalkyl, aryl or heteroaryl. No examples,wherein both the 2- and 3-position of the indole is directly substitutedby a cyclic moiety, are disclosed.

WO2008/003736 discloses azaindoles of Formula (N)

wherein R² and R³ can independently comprise a saturatednitrogen-containing heterocyclic moiety (e.g. piperidine) while m can be0. According claim 8, Q can represent the protecting group —SO₂-Ph. Noexamples, wherein both the 2- and 3-position of the indole is directlysubstituted by a cyclic moiety, are disclosed.

WO2007/075555 discloses CB₁ antagonists of Formula (P)

wherein R¹ can be selected from a broad range of substituents includinga substituted indole while X can represent a bond. The only examplewhere a cyclic moiety is linked to the 3-position of the indole isstructure P1. More specifically, indole derivatives of Formula (P) aredescribed in WO20041000831 as histamine H3 antagonist, again withstructure P1 as example.

WO2007/134169 and WO2006/050236 disclose indole derivatives of Formula(Q) as inhibitors of TNF-α production

wherein X can be SO₂, Y can be selected from a broad range ofsubstituents including cycloalkyl, heterocycloalkyl, aryl andheterocycle while Z has to be selected from —B(OR)₂, —CONROR and—N(OR)COR (with R═H or alkyl). R³ and R⁸ can be independently selectedfrom a broad range of substituents including cycloalkyl and a 5- or6-membered organic ring. No examples, wherein both the 2- and 3-positionof the indole is substituted by a cyclic moiety, are disclosed.

WO2005/034941 discloses bicyclic structures of Formula (R) as inhibitorsfor hepatitis C virus polymerase

wherein Ar¹ and Ar are 5- to 10-membered aromatic rings, A¹ can be acycloalkyl (optionally substituted with alkoxy) and n can be 0. Theclosest examples to the present invention are structure R1 and R2.

WO2005/14000 discloses indoles of Formula (S) for the treatment of5-HT₆-receptor-related diseases such as obesity and CNS disorders

wherein R¹ represents a nitrogen-attached saturated or unsaturatedheterocyclic ring system, R² can be selected from a broad range ofsubstituents including a saturated or unsaturated cycloalkyl, n isselected from 0 to 4 and residue A and B form a saturated or unsaturatedcycloalkyl ring. No examples, wherein both the 2- and 3-position of theindole is directly substituted (i.e. n=0) by a cyclic moiety, aredisclosed.

WO2002/51837 and WO2002/36562 disclose bicyclic structures of Formulae(T) and (T1), respectively, for the treatment of 5-HT₆-receptor-relateddiseases

wherein X and Y can independently represent a carbon atom, which isoptionally substituted with an aryl or heteroaryl moiety, R⁶ may alsorepresent an optionally substituted aryl or heteroaryl moiety. Thecyclic moiety on the left-hand-side of Formula (T1) is usuallypiperazine. No examples, wherein both the 2- and 3-position of the(aza)indole is substituted by a cyclic moiety (e.g. aryl or heteroaryl),are disclosed. The closest example is structure T1.

WO2002/32863 discloses indoles of Formula (U) for the treatment of5-HT₆-receptor-related diseases

wherein Ar can be selected from optionally substituted phenyl, naphthylor 5- to 10-membered mono- or bicyclic heterocyclic moieties, R² can bean unsubstituted phenyl and R³ is selected from hydrogen or3-(1-azabicyclo[2.2.2]oct-2-en)yl. However no example with suitablesubstitution at 2- and 3-position of the indole is shown—the closestexamples are structure U1 and U2.

WO9921851 discloses structures of Formula (V) as agricultural orhorticultural fungicides

wherein A can be selected from a very broad range of cyclic systemsincluding optionally substituted indole. However no example withsuitable substitution at 2- and 3-position of the indole is shown; theclosest example is structure V1.

WO9857931 and WO9822452 disclose bicyclic structures of Formulae (W) and(W1), respectively, as antimicrobial agents

wherein R² can be selected from a very broad range of residues includingaryl and heteroaryl; and Y can represent NR, with R selected from a verybroad range of residues including a arylsulfonyl moiety. No example withsubstitution at 2- and 3-position of the indole is shown; the closestexample is structure W1.

WO9822457 discloses bicyclic structures of Formula (X) asanti-inflammatory agents

wherein R¹⁰ can be selected from a very broad range of substituentsincluding SO₂R³⁰; and wherein R¹¹, R¹², R³⁰ can be selected fromoptionally substituted aryl and heteroaryl. However no example is shown,where R¹⁰ has indeed a SO₂-connected moiety.

WO2001/30343, WO2000/46199, WO2000/46197, WO2000/46195, JP06145150,EP0535926, EP0535925 describe indole derivatives, where in 2-position ofthe indole moiety a 1H- or 2H-tetrazol-5-yl moiety can be attached asonly possible cyclic moiety, which functions as a carboxylic acidbioisostere. The only example with such a directly connected tetrazolemoiety is disclosed in JP06145150 (Structure Y1).

WO2008/119657 describes imidazolidinone derivatives of Formula (Z)binding to LXR with representative example (Z1):

The following four structures were found to be weak binder on anothernuclear receptor target and therefor were mentioned as initial hits in aconfidential collaboration with another pharma company:

SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I)

a glycine conjugate, tauro conjugate, enantiomer, diastereomer,tautomer, N-oxide, solvate, prodrug and pharmaceutically acceptable saltthereof,

wherein cycle A, B, C, D and residue L and R¹ are defined as in claim 1.

The compounds of the present invention have a similar or better LXRinverse agonistic activity compared to the known LXR inverse agonists.Furthermore, the compounds of the present invention exhibit anadvantageous liver/blood-ratio after oral administration so thatdisruption of the anti-atherosclerotic reverse cholesterol transportgoverned by LXR in peripheral macrophages can be avoided. Theincorporation of an acidic moiety (or a bioisoster thereof) can improveadditional parameters, e.g. microsomal stability, solubility andlipophilicity.

Thus, the present invention further relates to a pharmaceuticalcomposition comprising a compound according to Formula (I) and at leastone pharmaceutically acceptable carrier or excipient.

The present invention is further directed to compounds according toFormula (I) for use in the prophylaxis and/or treatment of diseasesmediated by LXRs.

Accordingly, the present invention relates to the prophylaxis and/ortreatment of non-alcoholic fatty liver disease, non-alcoholicsteatohepatitis, liver inflammation, liver fibrosis, obesity, insulinresistance, type II diabetes, familial hypercholesterolemia,hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiacsteatosis, cancer, viral myocarditis and hepatitis C virus infection.

DETAILED DESCRIPTION OF THE INVENTION

The desired properties of a LXR modulator in conjunction withhepatoselectivity, can be yielded with compounds that follow thestructural pattern represented by Formula (I)

a glycine conjugate, tauro conjugate, enantiomer, diastereomer,tautomer, N-oxide, solvate, prodrug and pharmaceutically acceptable saltthereof, wherein

is an annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms independentlyselected from N, O and S, wherein this cycle is unsubstituted orsubstituted with 1 to 4 substituents independently selected from thegroup consisting of halogen, CN, SF₅, NO₂, C₁₋₆-alkyl, oxo,C₀₋₆-alkylene-OR¹¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R¹¹, C₀₋₆-alkylene-NR¹¹S(O)₂R¹¹,C₀₋₆-alkylene-S(O)₂NR¹¹R¹², C₀₋₆-alkylene-NR¹¹S(O)₂NR¹¹R¹²,C₀₋₆-alkylene-CO₂R¹¹, O—C₁₋₆-alkylene-CO₂R¹¹, C₀₋₆-alkylene-O—COR¹¹,C₀₋₆-alkylene-CONR¹¹R¹², C₀₋₆-alkylene-NR¹¹—COR¹¹,C₀₋₆-alkylene-NR¹¹—CONR¹¹R¹², C₀₋₆-alkylene-O—CONR¹¹R¹²,C₀₋₆alkylene-NR¹¹—CO₂R¹¹ and C₀₋₆-alkylene-NR¹¹R¹²,

-   -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; and

wherein optionally two adjacent substituents on the aryl or heteroarylmoiety form a 5- to 8-membered partially unsaturated cycle optionallycontaining 1 to 3 heteroatoms independently selected from O, S or N, and

-   -   wherein the new formed cycle is unsubstituted or substituted        with 1 to 3 substituents independently selected from halogen,        CN, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl,        halo-(3- to 6-membered cycloalkyl), 3- to 6-membered        heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH,        oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

is selected from the group consisting of 3- to 10-membered cycloalkyl,3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatomsindependently selected from N, O and S, 6- to 14-membered aryl and 5- to14-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1 to 6 substituents        independently selected from the group consisting of halogen, CN,        SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3-        to 6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered        heterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹,        C₀₋₆-alkylene-NR²¹S(O)₂R²¹, C₀₋₆-alkylene-S(O)₂NR²¹R²²,        C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²², C₀₋₆-alkylene-CO₂R²¹,        O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹,        C₀₋₆-alkylene-CONR²¹R²², C₀₋₆-alkylene-NR²¹—COR²¹,        C₀₋₆-alkylene-NR²¹—CONR²¹R²², C₀₋₆-alkylene-O—CONR²¹R²²,        C₀₋₆-alkylene-NR²¹—CO₂R²¹ and C₀₋₆-alkylene-NR²¹R²²,    -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the aryl orheteroaryl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C4-alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl orheterocycloalkyl moiety form a 5- to 6-membered unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N,

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;        is selected from the group consisting of 6- or 10-membered aryl        and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms        independently selected from N, O and S,    -   wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1 to 4 substituents        independently selected from the group consisting of halogen, CN,        SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR³¹, C₀₋₆-alkylene-(3-        to 6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered        heterocycloalkyl), C₀₋₆-alkylene-(6-membered aryl),        C₀₋₆-alkylene-(5- to 6-membered heteroaryl),        C₀₋₆-alkylene-S(O)_(n)R³¹, C₀₋₆-alkylene-NR³¹S(O)₂R³¹,        C₀₋₆-alkylene-S(O)₂NR³¹R³², C₀₋₆-alkylene-NR³¹S(O)₂NR³¹R³²,        C₀₋₆-alkylene-CO₂R³¹, O—C₀₋₆-alkylene-CO₂R³¹,        C₀₋₆-alkylene-O—COR³¹, C₀₋₆-alkylene-CONR³¹R³²,        C₀₋₆-alkylene-NR³¹—COR³¹, C₀₋₆-alkylene-NR³¹—CONR³¹R³²,        C₀₋₆-alkylene-O—CONR³¹R³², C₀₋₆-alkylene-NR³¹—CO₂R³¹ and        C₀₋₆-alkylene-NR³¹R³²,    -   wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is unsubstituted or substituted with 1 to 6        substituents independently selected from halogen, CN, oxo,        hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the aryl orheteroaryl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;        is selected from the group consisting of 3- to 10-membered        cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 3        heteroatoms independently selected from N, O and S, 6- to        14-membered aryl and 5- to 14-membered heteroaryl containing 1        to 4 heteroatoms independently selected from N, O and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl areunsubstituted or substituted with 1 to 6 substituents independentlyselected from the group consisting of halogen, CN, SF₅, NO₂, oxo,C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3- to 6-memberedcycloalkyl), C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R²¹, C₀₋₆-alkylene-NR²¹S(O)₂R²¹,C₀₋₆-alkylene-S(O)₂NR²¹R²², C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²²,C₀₋₆-alkylene-CR⁴¹(═N—OR⁴¹), C₀₋₆-alkylene-CO₂R²¹,O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹, C₀₋₆-alkylene-CONR²¹R²²,C₀₋₆-alkylene-NR²¹—COR²¹, C₀₋₆-alkylene-NR²¹—CONR²¹R²²,C₀₋₆-alkylene-O—CONR²¹R²², C₀₋₆-alkylene-NR²¹—CO₂R²¹ andC₀₋₆-alkylene-NR²¹R²²,

-   -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, CO—OC₁₋₄-alkyl,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the aryl orheteroaryl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl orheterocycloalkyl moiety form a 5- to 6-membered unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N,

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

wherein

has a substituent from above in 1,2-orientation regarding to theconnection towards

or has an annelated additional cycle in 1,2-orientation;

L is selected from the group consisting of a bond, C₁₋₆-alkylene,C₂₋₆-alkenylene, C₂₋₆-alkinylene, 3- to 10-membered cycloalkylene, 3- to10-membered heterocycloalkylene containing 1 to 4 heteroatomsindependently selected from N, O and S, 6- or 10-membered arylene and 5-to 10-membered heteroarylene containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein alkylene, alkenylene, alkinylene, cycloalkylene,        heterocycloalkylene, arylene and heteroarylene are unsubstituted        or substituted with 1 to 6 substituents independently selected        from the group consisting of halogen, CN, SF₅, NO₂, oxo,        C₁₋₄-alkyl, C₀₋₆-alkylene-OR⁴¹, C₀₋₆-alkylene-(3- to 6-membered        cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),        C₀₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-NR⁴¹S(O)₂R⁴¹,        C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴²,        C₀₋₆-alkylene-CO₂R⁴¹, O—C₁₋₆-alkylene-CO₂R⁴¹,        C₀₋₆-alkylene-O—COR⁴¹, C₀₋₆-alkylene-CONR⁴¹R⁴²,        C₀₋₆-alkylene-NR⁴¹—COR⁴¹, C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴²,        C₀₋₆-alkylene-O—CONR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹ and        C₀₋₆-alkylene-NR⁴¹R⁴²,    -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the arylene andheteroarylene moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

R¹ is selected from the group consisting of H, halogen, CN, SF₅, NO₂,oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR⁴¹, Y—C₀₋₆-alkylene-(3- to 6-memberedcycloalkyl), Y—C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),Y—C₀₋₆-alkylene-(6-membered aryl), Y—C₀₋₆-alkylene-(5- to 6-memberedheteroaryl), C₀₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵,X—C₁₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵, C₀₋₆-alkylene-S(O)_(n)R⁴¹,X—C₀₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)₂R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)₂R⁴¹, C₀₋₆-alkylene-NR⁴¹S(O)₂R⁴¹,X—C₁₋₆-alkylene-NR⁴¹S(O)₂R⁴¹, C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-SO₃R⁴¹,X—C₁₋₆-alkylene-SO₃R⁴¹, C₀₋₆-alkylene-CO₂R⁴¹, X—C₁₋₆-alkylene-CO₂R⁴¹,C₀₋₆-alkylene-O—COR⁴¹, X—C₁₋₆-alkylene-O—COR⁴¹, C₀₋₆-alkylene-CONR⁴¹R⁴²,X—C₁₋₆-alkylene-CONR⁴¹R⁴², C₀₋₆-alkylene-CONR⁴¹OR⁴¹,X—C₁₋₆-alkylene-CONR⁴¹OR⁴¹, C₀₋₆-alkylene-CONR⁴¹SO₂R⁴¹,X—C₁₋₆-alkylene-CONR⁴¹SO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹—COR⁴¹,X—C₁₋₆—C₀₋₆-alkylene-NR⁴¹—COR⁴¹, C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴², C₀₋₆-alkylene-O—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-O—CONR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹,X—C₁₋₆-alkylene-NR⁴¹—CO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹R⁴²,

-   -   wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is unsubstituted or substituted with 1 to 6        substituents independently selected from halogen, CN, oxo,        hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the aryl and        heteroaryl moiety form a 5- to 8-membered partially unsaturated        cycle optionally containing 1 to 3 heteroatoms independently        selected from O, S or N, and    -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

R¹¹, R¹², R²¹, R²², R³¹, R, R⁴¹, R⁴², R⁵¹ are independently selectedfrom H and C₁₋₄-alkyl,

-   -   wherein alkyl is unsubstituted or substituted with 1 to 3        substituent independently selected from halogen, CN, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to        6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl,        halo-(3- to 6-membered heterocycloalkyl), OH, oxo, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H, O—C₁₋₄-alkyl        and O-halo-C₁₋₄-alkyl;

or R¹¹ and R¹², R²¹ and R²², R³¹ and R³², R⁴¹ and R⁴², respectively,when taken together with the nitrogen to which they are attachedcomplete a 3- to 6-membered ring containing carbon atoms and optionallycontaining 1 or 2 heteroatoms independently selected from O, S or N; and

-   -   wherein the new formed cycle is unsubstituted or substituted        with 1 to 3 substituents independently selected from halogen,        CN, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl,        halo-(3- to 6-membered cycloalkyl), 3- to 6-membered        heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH,        oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H,        O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

R⁷¹ is independently selected from H, CN; NO₂, C₁₋₄-alkyl andC(O)—OC₁₋₄-alkyl,

-   -   wherein alkyl is unsubstituted or substituted with 1 to 3        substituents independently selected from halogen, CN,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl,        halo-(3- to 6-membered cycloalkyl), 3- to 6-membered        heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH,        oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H,        O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

R⁷⁵ is independently selected from C₁₋₄-alkyl, 3- to 6-memberedcycloalkyl, 3- to 6-membered heterocycloalkyl, 6-membered aryl and 5- to6-membered heteroaryl,

-   -   wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl        is unsubstituted or substituted with 1 to 3 substituents        independently selected from halogen, CN, Me, Et, CHF₂, CF₃, OH,        oxo, CO₂H, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H, OMe, OEt, OCHF₂,        and OCF₃;

X is independently selected from O, NR⁵¹, S(O)_(n), S(═NR⁷¹),S(O)(═NR⁷¹) and S(═NR⁷¹)₂;

Y is independently selected from a bond, O, NR⁵¹, S(O), S(═NR⁷¹),S(O)(═NR⁷¹) and S(═NR⁷¹)₂;

n is independently selected from 0 to 2;

and with the proviso, that the following structures are excluded:

In a preferred embodiment in combination with any of the above or belowembodiments

is an annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms independentlyselected from N, O and S, wherein this cycle is unsubstituted orsubstituted with 1 to 4 substituents independently selected from thegroup consisting of halogen, CN, SF₅, NO₂, C₁₋₆-alkyl, oxo,C₀₋₆-alkylene-OR¹¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R¹¹, C₀₋₆-alkylene-NR¹¹S(O)₂R¹,C₀₋₆-alkylene-S(O)₂NR¹¹R¹², C₀₋₆-alkylene-NR¹¹S(O)₂NR¹¹R¹²,C₀₋₆-alkylene-CO₂R¹¹, O—C₁₋₆-alkylene-CO₂R¹¹, C₀₋₆-alkylene-O—COR¹¹,C₀₋₆-alkylene-CONR¹¹R¹², C₀₋₆-alkylene-NR¹¹—COR¹¹,C₀₋₆-alkylene-NR¹¹—CONR¹¹R¹², C₀₋₆-alkylene-O—CONR¹¹R¹²,C₀₋₆-alkylene-NR¹¹—CO₂R¹¹ and C₀₋₆-alkylene-NR¹¹R¹²,

-   -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; and

wherein optionally two adjacent substituents on the aryl or heteroarylmoiety form a 5- to 8-membered partially unsaturated cycle optionallycontaining 1 to 3 heteroatoms independently selected from O, S or N, and

wherein the new formed cycle is unsubstituted or substituted with 1 to 3substituents independently selected from halogen, CN, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-memberedcycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-memberedheterocycloalkyl), OH, oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a more preferred embodiment in combination with any of the above orbelow embodiments

is an annelated phenyl, thiophenyl, thiazolyl, pyridyl, pyrimidinyl,pyridazinyl and pyrazinyl, wherein this cycle is unsubstituted orsubstituted with 1 to 4 substituents independently selected from thegroup consisting of halogen, CN, SF₅, NO₂, C₁₋₆-alkyl, oxo,C₀₋₆-alkylene-OR¹¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R¹¹, C₀₋₆-alkylene-NR¹¹S(O)₂R¹¹,C₀₋₆-alkylene-S(O)₂NR¹¹R¹², C₀₋₆-alkylene-NR¹¹S(O)₂NR¹¹R¹²,C₀₋₆-alkylene-CO₂R¹¹, O—C₁₋₆-alkylene-CO₂R¹¹, C₀₋₆alkylene-O—COR¹¹,C₀₋₆-alkylene-CONR¹¹R¹², C₀₋₆-alkylene-NR¹¹—COR¹¹,C₀₋₆-alkylene-NR¹¹—CONR¹¹R¹², C₀₋₆-alkylene-O—CONR¹¹R¹²,C₀₋₆-alkylene-NR¹¹—CO₂R¹¹ and C₀₋₆-alkylene-NR¹¹R¹²,

-   -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In an even more preferred embodiment in combination with any of theabove or below embodiments

is selected from

wherein

is unsubstituted or substituted with 1 to 3 substituents independentlyselected from the group consisting of F, Cl, Br, CN, OH, oxo,C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl, O-halo-C₁₋₄-alkyl, NH₂,NHC₁₋₄-alkyl, N(C₁₋₄-alkyl)₂, SO₂—C₁₋₄-alkyl and SO₂-halo-C₁₋₄-alkyl.

In a most preferred embodiment in combination with any of the above orbelow embodiments

wherein

is unsubstituted or substituted with 1 to 3 substituents independentlyselected from the group consisting of F, Cl, Br, CN, Me, Et, CF₃, CHF₂,OH, OMe, OCF₃ and OCHF₃.

In a preferred embodiment in combination with any of the above or belowembodiments

is selected from the group consisting of 3- to 10-membered cycloalkyl,3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatomsindependently selected from N, O and S, 6- to 14-membered aryl and 5- to14-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1 to 6 substituents        independently selected from the group consisting of halogen, CN,        SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3-        to 6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered        heterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹,        C₀₋₆-alkylene-NR²¹S(O)₂R²¹, C₀₋₆-alkylene-S(O)₂NR²¹R²²,        C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²², C₀₋₆-alkylene-CO₂R²¹,        O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹,        C₀₋₆-alkylene-CONR²¹R²², C₀₋₆-alkylene-NR²¹—COR²¹,        C₀₋₆-alkylene-NR²¹—CONR²¹R²², C₀₋₆-alkylene-O—CONR²¹R²²,        C₀₋₆-alkylene-NR²¹—CO₂R²¹ and C₀₋₆-alkylene-NR²¹R²²,    -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the aryl orheteroaryl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the        cycloalkyl or heterocycloalkyl moiety form a 5- to 6-membered        unsaturated cycle optionally containing 1 to 3 heteroatoms        independently selected from O, S or N,

wherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a more preferred embodiment in combination with any of the above orbelow embodiments

is selected from the group consisting of phenyl, pyridyl and thiophenyl,

-   -   wherein phenyl, pyridyl and thiophenyl are substituted with 1 to        4 substituents independently selected from the group consisting        of halogen, CN, SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹,        C₀₋₆-alkylene-(3- to 6-membered cycloalkyl), C₀₋₆-alkylene-(3-        to 6-membered heterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹,        C₀₋₆-alkylene-NR²¹S(O)₂R²¹, C₀₋₆-alkylene-S(O)₂NR²¹R²²,        C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²², C₀₋₆-alkylene-CO₂R²¹,        O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹,        C₀₋₆-alkylene-CONR²¹R²², C₀₋₆-alkylene-NR²¹—COR²¹,        C₀₋₆-alkylene-NR²¹—CONR²¹R²², C₀₋₆-alkylene-O—CONR²¹R¹¹,        C₀₋₆-alkylene-NR²¹—CO₂R²¹ and C₀₋₆-alkylene-NR²¹R²²,    -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,        halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the phenyl andpyridyl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a similar more preferred embodiment in combination with any of theabove or below embodiments

is selected from the group consisting of phenyl, naphthyl, pyridyl,pyrimidinyl, thiophenyl, thiazolyl, cyclopentyl, cyclohexyl,bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl,pentacyclo[4.2.0.0^(2,5).0^(3,8).0^(4,7)]octyl and piperidinyl,

wherein the cycle is unsubstituted or substituted with 1 to 3substituents independently selected from the group consisting of F, Cl,Br, CN, OH, oxo, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl,O-halo-C₁₋₄-alkyl, C₁₋₄-alkyl-OH and halo-C₁₋₄-alkyl-OH; and whereinoptionally two adjacent substituents on the phenyl ring form together a—(CH₂)₃—, —(CH₂)₄—, —OCF₂O— and —OCH₂O— group. In an even more preferredembodiment in combination with any of the above or below embodiments

is selected from the group consisting of phenyl and pyridyl,

wherein phenyl and pyridyl is substituted with 1 to 2 substituentsindependently selected from the group consisting of F, Cl, CN, CF₃, CH₂Fand CHF₂.

In a most preferred embodiment in combination with any of the above orbelow embodiments

is 4-difluoromethylphenyl.

In a preferred embodiment in combination with any of the above or belowembodiments

is selected from the group consisting of 6- or 10-membered aryl and 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms independentlyselected from N, O and S,

-   -   wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1 to 4 substituents        independently selected from the group consisting of halogen, CN,        SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR³¹, C₀₋₆-alkylene-(3-        to 6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered        heterocycloalkyl), C₀₋₆-alkylene-(6-membered aryl),        C₀₋₆-alkylene-(5- to 6-membered heteroaryl),        C₀₋₆-alkylene-S(O)_(n)R³¹, C₀₋₆-alkylene-NR³¹S(O)₂R³¹,        C₀₋₆-alkylene-S(O)₂NR³¹R³², C₀₋₆-alkylene-NR³¹S(O)₂NR³¹R³²,        C₀₋₆-alkylene-CO₂R³¹, O—C₁₋₆-alkylene-CO₂R³¹,        C₀₋₆-alkylene-O—COR³¹, C₀₋₆-alkylene-CONR³¹R³²,        C₀₋₆-alkylene-NR³¹—COR³¹, C₀₋₆-alkylene-NR³¹—CONR³¹R³²,        C₀₋₆-alkylene-O—CONR³¹R³², C₀₋₆-alkylene-NR³¹—CO₂R³¹ and        C₀₋₆-alkylene-NR³¹R³²,    -   wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is unsubstituted or substituted with 1 to 6        substituents independently selected from halogen, CN, oxo,        hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the aryl or        heteroaryl moiety form a 5- to 8-membered partially unsaturated        cycle optionally containing 1 to 3 heteroatoms independently        selected from O, S or N, and

wherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a more preferred embodiment in combination with any of the above orbelow embodiments

is selected from the group consisting of phenyl, pyridyl and thiophenyl,

-   -   wherein phenyl, pyridyl and thiophenyl are unsubstituted or        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, CN, SF₅, NO₂, oxo, C₁₋₄alkyl,        C₀₋₆-alkylene-OR³¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),        C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),        C₀₋₆-alkylene-(6-membered aryl), C₀₋₆-alkylene-(5- to 6-membered        heteroaryl), C₀₋₆-alkylene-S(O)_(n)R³¹,        C₀₋₆-alkylene-NR³¹S(O)₂R³¹, C₀₋₆-alkylene-S(O)₂NR³¹R³²,        C₀₋₆-alkylene-NR³¹S(O)₂NR³¹R³², C₀₋₆-alkylene-CO₂R³¹,        O—C₁₋₄-alkylene-CO₂R³¹, C₀₋₆-alkylene-O—COR³¹,        C₀₋₆-alkylene-CONR³¹R³², C₀₋₆-alkylene-NR³¹—COR³¹,        C₀₋₆-alkylene-NR³¹—CONR³¹R³², C₀₋₆-alkylene-O—CONR³¹R³²,        C₀₋₆-alkylene-NR³¹—CO₂R³¹ and C₀₋₆-alkylene-NR³¹R³²,    -   wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is unsubstituted or substituted with 1 to 6        substituents independently selected from halogen, CN, oxo,        hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein residue -L-R¹ is linked in 1,3-orientation regarding theconnection towards

and L is not a bond.

In an even more preferred embodiment in combination with any of theabove or below embodiments

is selected from phenyl, pyridyl and thiophenyl; wherein phenyl, pyridyland thiophenyl is unsubstituted or substituted with 1 to 3 substituentsindependently selected from the group consisting of F, Cl, CN, OH, oxo,C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄alkyl; andwherein the residue -L-R¹ is linked in 1,3-orientation regarding theconnection towards

and L is not a bond.

In a most preferred embodiment in combination with any of the above orbelow embodiments

is phenyl, wherein phenyl is unsubstituted or substituted with F, Cl andMe; an wherein the residue -L-R¹ is linked in 1,3-orientation regardingthe connection towards

and L is not a bond.

In a preferred embodiment in combination with any of the above or belowembodiments

L is selected from the group consisting of a bond, C₁₋₆-alkylene,C₂₋₆-alkenylene, C₂₋₆-alkinylene, 3- to 10-membered cycloalkylene, 3- to10-membered heterocycloalkylene containing 1 to 4 heteroatomsindependently selected from N, O and S, 6- or 10-membered arylene and 5-to 10-membered heteroarylene containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein alkylene, alkenylene, alkinylene, cycloalkylene,        heterocycloalkylene, arylene and heteroarylene are unsubstituted        or substituted with 1 to 6 substituents independently selected        from the group consisting of halogen, CN, SF₅, NO₂, oxo,        C₁₋₄-alkyl, C₀₋₆-alkylene-OR⁴¹, Cow-alkylene-(3- to 6-membered        cycloalkyl), Cow-alkylene-(3- to 6-membered heterocycloalkyl),        C₀₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-NR⁴¹S(O)₂R⁴¹,        C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴²,        C₀₋₆-alkylene-CO₂R⁴¹, O—C₁₋₆-alkylene-CO₂R⁴¹,        C₀₋₆-alkylene-O—COR⁴¹, C₀₋₆-alkylene-CONR⁴¹R⁴²,        C₀₋₆-alkylene-NR⁴¹—COR⁴¹, C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴²,        C₀₋₆-alkylene-O—CONR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹ and        C₀₋₆-alkylene-NR⁴¹R⁴²,        -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is            unsubstituted or substituted with 1 to 6 substituents            independently selected from halogen, CN, oxo, hydroxy, CO₂H,            CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the arylene        and heteroarylene moiety form a 5- to 8-membered partially        unsaturated cycle optionally containing 1 to 3 heteroatoms        independently selected from O, S or N, and        -   wherein this additional cycle is unsubstituted or            substituted with 1 to 4 substituents independently selected            from halogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a more preferred embodiment in combination with any of the above orbelow embodiments

L is selected from the group consisting of 3- to 10-memberedcycloalkylene, 3- to 10-membered heterocycloalkylene containing 1 to 4heteroatoms independently selected from N, O and S, 6-membered aryleneand 5- to 6-membered heteroarylene containing 1 to 2 heteroatomsindependently selected from N, O and S,

-   -   wherein cycloalkylene, heterocycloalkylene, arylene and        heteroarylene are unsubstituted or substituted with 1 to 6        substituents independently selected from the group consisting of        halogen, CN, SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR⁴¹,        C₀₋₆-alkylene-(3- to 6-membered cycloalkyl), C₀₋₆-alkylene-(3-        to 6-membered heterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R¹¹,        C₀₋₆-alkylene-NR⁴¹S(O)₂R⁴¹, C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴²,        C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-CO₂R⁴¹,        O—C₁₋₆-alkylene-CO₂R⁴¹, C₀₋₆-alkylene-O—COR⁴¹,        C₀₋₆-alkylene-CONR¹¹R⁴², C₀₋₆-alkylene-NR⁴¹—COR⁴¹,        C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴², C₀₋₆-alkylene-O—CONR⁴¹R⁴²,        C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹ and C₀₋₆-alkylene-NR⁴¹R⁴²,        -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is            unsubstituted or substituted with 1 to 6 substituents            independently selected from halogen, CN, oxo, hydroxy, CO₂H,            CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the arylene        and heteroarylene moiety form a 5- to 8-membered partially        unsaturated cycle optionally containing 1 to 3 heteroatoms        independently selected from O, S or N, and        -   wherein this additional cycle is unsubstituted or            substituted with 1 to 4 substituents independently selected            from halogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In an even more preferred embodiment in combination with any of theabove or below embodiments

-L-R¹ is selected from

wherein the cycle is unsubstituted or substituted with 1 to 4substituents independently selected from the group consisting of F, Cl,Br, CN, OH, oxo, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl,O-halo-C₁₋₄-alkyl, C₁₋₄-alkyl-OH, halo-C₁₋₄-alkyl-OH, SO₂—C₁₋₄-alkyl andSO₂-halo-C₁₋₄-alkyl; and wherein optionally two adjacent substituents onthe phenyl ring form together a —(CH₂)₃—, —(CH₂)₄—, —OCF₂O— and —OCH₂O—group.

In a most preferred embodiment in combination with any of the above orbelow embodiments

-L-R¹ is selected from

wherein phenyl is unsubstituted or substituted with 1 to 4 substituentsindependently selected from the group consisting of F, Cl, CN, OH, Meand OMe.

In a preferred embodiment in combination with any of the above or belowembodiments

R¹ is selected from the group consisting of H, halogen, CN, SF₅, NO₂,oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR⁴¹, Y—C₀₋₆-alkylene-(3- to 6-memberedcycloalkyl), Y—C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),Y—C₀₋₆-alkylene-(6-membered aryl), Y—C₀₋₆-alkylene-(5- to 6-memberedheteroaryl), C₀₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵,X—C₁₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵, C₀₋₆-alkylene-S(O)_(n)R⁴¹,X—C₁₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)₂R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)₂R⁴¹, C₀₋₆-alkylene-NR⁴¹S(O)₂R⁴¹,X—C₁₋₆-alkylene-NR⁴¹S(O)₂R⁴¹, C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-SO₃R⁴¹,X—C₁₋₆-alkylene-SO₃R⁴¹, C₀₋₆-alkylene-CO₂R⁴¹, X—C₁₋₆-alkylene-CO₂R⁴¹,C₀₋₆-alkylene-O—COR⁴¹, X—C₁₋₆-alkylene-O—COR⁴¹, C₀₋₆-alkylene-CONR⁴¹R⁴²,X—C₁₋₆-alkylene-CONR⁴¹R⁴², C₀₋₆-alkylene-CONR⁴¹OR⁴¹,X—C₁₋₆-alkylene-CONR⁴¹OR⁴¹, C₀₋₆-alkylene-CONR⁴¹SO₂R⁴¹,X—C₁₋₆-alkylene-CONR⁴¹SO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹—COR⁴¹,X—C₁₋₆—C₀₋₆-alkylene-NR⁴¹—COR⁴¹, C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴², C₀₋₆-alkylene-O—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-O—CONR⁴¹R⁴², C₀₋₆-alkylene-NR¹—CO₂R⁴¹,X—C₁₋₆-alkylene-NR⁴¹—CO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹R⁴²,

-   -   wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is unsubstituted or substituted with 1 to 6        substituents independently selected from halogen, CN, oxo,        hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the aryl and        heteroaryl moiety form a 5- to 8-membered partially unsaturated        cycle optionally containing 1 to 3 heteroatoms independently        selected from O, S or N, and

wherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl.

In a more preferred embodiment in combination with any of the above orbelow embodiments

R¹ is selected from CO₂H, tetrazole, CH₂CO₂H, OCH₂CO₂H, SO₂CH₂CO₂H,CHMeCO₂H, CMe₂CO₂H, C(OH)MeCO₂H, CONHSO₂Me and CONH(OH); and optionallythe glycine and tauro conjugate thereof.

In a most preferred embodiment in combination with any of the above orbelow embodiments

R¹ is selected from CO₂H and C(OH)MeCO₂H; and optionally the glycine andtauro conjugate thereof.

In a preferred embodiment in combination with any of the above or belowembodiments

-L-R¹ is selected from

and optionally the glycine and tauro conjugate thereof.

In amore preferred embodiment in combination with any of the above orbelow embodiments

-L-R¹ is selected from

and optionally the glycine and tauro conjugate thereof.

In a most preferred embodiment in combination with any of the above orbelow embodiments

-L-R¹ is selected from

and optionally the glycine and tauro conjugate thereof.

In a preferred embodiment in combination with any of the above or belowembodiments

is selected from the group consisting of 3- to 10-membered cycloalkyl,3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatomsindependently selected from N, O and S, 6- to 14-membered aryl and 5- to14-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1 to 6 substituents        independently selected from the group consisting of halogen, CN,        SF₅, NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3-        to 6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-membered        heterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹,        C₀₋₆-alkylene-NR²¹S(O)₂R²¹, C₀₋₆-alkylene-S(O)₂NR²¹R²²,        C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²², C₀₋₆-alkylene-CR⁴¹(═N—OR⁴¹),        C₀₋₆-alkylene-CO₂R²¹, O—C₁₋₆-alkylene-CO₂R²¹,        C₀₋₆-alkylene-O—COR²¹, C₀₋₆-alkylene-CONR²¹R²²,        C₀₋₆-alkylene-NR²¹—COR²¹, C₀₋₆-alkylene-NR²¹—CONR²¹R²²,        C₀₋₆-alkylene-O—CONR²¹R²², C₀₋₆-alkylene-NR²¹—CO₂R²¹ and        C₀₋₆-alkylene-NR^(2′)R²²,    -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is        unsubstituted or substituted with 1 to 6 substituents        independently selected from halogen, CN, oxo, hydroxy, CO₂H,        CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, CO—OC₁₋₄-alkyl,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the aryl orheteroaryl moiety form a 5- to 8-membered partially unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, and

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl orheterocycloalkyl moiety form a 5- to 6-membered unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N,

-   -   wherein this additional cycle is unsubstituted or substituted        with 1 to 4 substituents independently selected from halogen,        CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,        C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

wherein

has a substituent from above in 1,2-orientation regarding to theconnection towards

or has an annelated additional cycle in 1,2-orientation.

In a more preferred embodiment in combination with any of the above orbelow embodiments

is selected from the group consisting of 6- or 10-membered aryl and 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S,

-   -   wherein aryl and heteroaryl are unsubstituted or substituted        with 1 to 6 substituents independently selected from the group        consisting of halogen, CN, SF₅, NO₂, oxo, C₁₋₄-alkyl,        C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),        C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),        C₀₋₆-alkylene-S(O)_(n)R²¹, C₀₋₆-alkylene-NR²¹S(O)₂R²¹,        C₀₋₆-alkylene-S(O)₂NR²¹R²², C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²²,        C₀₋₆-alkylene-CR⁴¹(═N—OR⁴¹), C₀₋₆-alkylene-CO₂R²¹,        O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹,        C₀₋₆-alkylene-CONR²¹R²², C₀₋₆-alkylene-NR²¹—COR²¹,        C₀₋₆-alkylene-NR²¹—CONR²¹R²², C₀₋₆-alkylene-O—CONR²¹R²²,        C₀₋₆-alkylene-NR²¹—CO₂R²¹ and C₀₋₆-alkylene-NR²¹R²²,        -   wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is            unsubstituted or substituted with 1 to 6 substituents            independently selected from halogen, CN, oxo, hydroxy, CO₂H,            CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, CO—OC₁₋₄-alkyl,            C₁₋₄alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and            O-halo-C₁₋₄-alkyl;    -   and wherein optionally two adjacent substituents on the aryl or        heteroaryl moiety form a 5- to 8-membered partially unsaturated        cycle optionally containing 1 to 3 heteroatoms independently        selected from O, S or N, and        -   wherein this additional cycle is unsubstituted or            substituted with 1 to 4 substituents independently selected            from halogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl,            CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl, halo-C₁₋₄-alkyl,            O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

wherein

has a substituent from above in 1,2-orientation regarding to theconnection towards

or has an annelated additional cycle in 1,2-orientation.

In an even more preferred embodiment in combination with any of theabove or below embodiments

is selected from the group consisting

wherein

R² is selected from Me, F, Cl, CN, Me, CHO, CHF₂, CF₃, SO₂Me,

and

wherein

is not further substituted or further substituted with 1 to 2substituents selected from the group consisting F, Cl, CN, Me, OMe, CHO,CHF₂ and CF₃.

In a most preferred embodiment in combination with any of the above orbelow embodiments

is selected from the group consisting of

In a preferred embodiment in combination with any of the above or belowembodiments Formula (I) contains a substituent selected from the groupconsisting of CO₂H, tetrazole, CONHSO₂Me and CONH(OH); and optionallythe glycine and tauro conjugate thereof.

In a more preferred embodiment in combination with any of the above orbelow embodiments Formula (I) contains a carboxylic acid moiety andoptionally the glycine and tauro conjugate thereof.

In a most preferred embodiment, the compound is selected from

or a glycine conjugate or tauro conjugate thereof; and

an enantiomer, diastereomer, tautomer, N-oxide, solvate, prodrug andpharmaceutically acceptable salt thereof.

In an upmost preferred embodiment, the compound is2-chloro-3′-(3-(2-cyanothiophen-3-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is2-chloro-3′-(3-(2-cyanothiophen-3-yl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

In a similar upmost preferred embodiment, the compound is2-chloro-3′-(3-(3-cyanopyrazin-2-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is2-chloro-3′-(3-(3-cyanopyrazin-2-yl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

In a similar upmost preferred embodiment, the compound is2-chloro-3′-(3-(2-cyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is2-chloro-3′-(3-(2-cyanophenyl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

In a similar upmost preferred embodiment, the compound is2-chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is2-chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

In a similar upmost preferred embodiment, the compound is3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-2,6-difluoro-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-2,6-difluoro-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

In a similar upmost preferred embodiment, the compound is2-chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-5-fluoro-[1,1′-biphenyl]-4-carboxylicacid or a glycine conjugate or tauro conjugate thereof and optionally apharmaceutically acceptable salt thereof. Even more preferred is2-chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-5-fluoro-[1,1′-biphenyl]-4-carboxylicacid and optionally a pharmaceutically acceptable salt thereof.

The invention also provides the compound of the invention for use as amedicament.

Also provided is the compound of the present invention for use in theprophylaxis and/or treatment of diseases amenable for treatment with LXRmodulators.

Also provided is the compound of the invention for use in treating a LXRmediated disease selected from non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, liver inflammation, liver fibrosis,obesity, insulin resistance, type II diabetes, familialhypercholesterolemia, hypercholesterolemia in nephrotic syndrome,metabolic syndrome, cardiac steatosis, cancer, viral myocarditis,hepatitis C virus infection or its complications, and unwantedside-effects of long-term glucocorticoid treatment in diseases such asrheumatoid arthritis, inflammatory bowel disease and asthma.

In a preferred embodiment, the disease is selected from non-alcoholicfatty liver disease, non-alcoholic steatohepatitis, liver inflammation,liver fibrosis, obesity, insulin resistance, type 11 diabetes, familialhypercholesterolemia, hypercholesterolemia in nephrotic syndrome,metabolic syndrome or cardiac steatosis.

In a similar preferred embodiment, the disease is cancer.

In a similar preferred embodiment, the disease is selected from viralmyocarditis, hepatitis C virus infection or its complications.

The invention further relates to a method for preventing and/or treatingdiseases mediated by LXRs, the method comprising administering acompound of the present invention in an effective amount to a subject inneed thereof.

More specifically, the invention relates to a method for preventing andtreating diseases selected from non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, liver inflammation, liver fibrosis,obesity, insulin resistance, type II diabetes, familialhypercholesterolemia, hypercholesterolemia in nephrotic syndrome,metabolic syndrome, cardiac steatosis, cancer, viral myocarditis,hepatitis C virus infection or its complications, and unwantedside-effects of long-term glucocorticoid treatment in diseases such asrheumatoid arthritis, inflammatory bowel disease and asthma.

Moreover, the invention also relates to the use of a compound accordingto the present invention in the preparation of a medicament for theprophylaxis and/or treatment of a LXR mediated disease.

More specifically, the invention relates to the use of a compoundaccording to the present invention in the preparation of a medicamentfor the prophylaxis and/or treatment of a LXR mediated disease, whereinthe disease is selected from non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, liver inflammation, liver fibrosis,obesity, insulin resistance, type II diabetes, familialhypercholesterolemia, hypercholesterolemia in nephrotic syndrome,metabolic syndrome, cardiac steatosis, cancer, viral myocarditis,hepatitis C virus infection or its complications, and unwantedside-effects of long-term glucocorticoid treatment in diseases such asrheumatoid arthritis, inflammatory bowel disease and asthma.

Also provided is a pharmaceutical composition comprising the compound ofthe invention and a pharmaceutically acceptable carrier or excipient.

In the context of the present invention “C₁₋₆-alkyl” means a saturatedalkyl chain having 1 to 6 carbon atoms which may be straight chained orbranched. Examples thereof include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl andisohexyl. Similarly, “C₁₋₄-alkyl” means a saturated alkyl chain having 1to 4 carbon atoms which may be straight chained or branched. Examplesthereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, andtert-butyl.

The term “halo-C₁₋₄-alkyl” means that one or more hydrogen atoms in thealkyl chain are replaced by a halogen. A preferred example thereof isCH₂F, CHF₂ and CF₃.

A “C₀₋₆-alkylene” means that the respective group is divalent andconnects the attached residue with the remaining part of the molecule.Moreover, in the context of the present invention, “C₀-alkylene” ismeant to represent a bond, whereas C₁-alkylene means a methylene linker,C₂-alkylene means a ethylene linker or a methyl-substituted methylenelinker and so on. In the context of the present invention, aC₀₋₆-alkylene preferably represents a bond, a methylene, a ethylenegroup or a propylene group.

Similarly, a “C₂₋₆-alkenylene” and a “C₂₋₆-alkinylene” means a divalentalkenyl or alkynyl group which connects two parts of the molecule.

A 3- to 10-membered cycloalkyl group means a saturated or partiallyunsaturated mono-, bi-, spiro- or multicyclic ring system comprising 3to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octanyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, adamantyland pentacyclo[4.2.0.0^(2.5).0^(3.8).0^(4.7)]octyl. Consequently, a 3-to 6-membered cycloalkyl group means a saturated or partiallyunsaturated mono-bi-, or spirocyclic ring system comprising 3 to 6carbon atoms whereas a 5- to 8-membered cycloalkyl group means asaturated or partially unsaturated mono-, bi-, or spirocyclic ringsystem comprising 5 to 8 carbon atoms.

A 3- to 10-membered heterocycloalkyl group means a saturated orpartially unsaturated 3 to 10 membered carbon mono-, bi-, spiro- ormulticyclic ring wherein 1, 2, 3 or 4 carbon atoms are replaced by 1, 2,3 or 4 heteroatoms, respectively, wherein the heteroatoms areindependently selected from N, O, S, SO and SO₂. Examples thereofinclude epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl tetrahydropyranyl, 1,4-dioxanyl, morpholinyl,4-quinuclidinyl, 1,4-dihydropyridinyl and 6-azabicyclo[3.2.1]octanyl.The heterocycloalkyl group can be connected with the remaining part ofthe molecule via a carbon, nitrogen (e.g. in morpholine or piperidine)or sulfur atom. An example for a S-linked heterocycloalkyl is the cyclicsulfonimidamide

A 5- to 14-membered mono-, bi- or tricyclic heteroaromatic ring system(within the application also referred to as heteroaryl) means anaromatic ring system containing up to 6 heteroatoms independentlyselected from N, O, S, SO and SO₂. Examples of monocyclic heteroaromaticrings include pyrrolyl, imidazolyl, furanyl, thiophenyl (thienyl),pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclicring system wherein the heteroatom(s) may be present in one or bothrings including the bridgehead atoms. Examples thereof includequinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl,benzofuranyl, benzoxazolyl, indolyl, indolizinyl 1,5-naphthyridinyl,1,7-naphthyridinyl and pyrazolo[1,5-a]pyrimidinyl. Examples of tricyclicheteroaromatic rings include acridinyl, benzo[b][1,5]naphthyridinyl andpyrido[3,2-b][1,5]naphthyridinyl.

The nitrogen or sulphur atom of the heteroaryl system may also beoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide.

If not stated otherwise, the heteroaryl system can be connected via acarbon or nitrogen atom. Examples for N-linked heterocycles are

A 6- to 14-membered mono-, bi- or tricyclic aromatic ring system (withinthe application also referred to as aryl) means an aromatic carbon cyclesuch as phenyl, naphthyl, anthracenyl or phenanthrenyl.

The term “N-oxide” denotes compounds, where the nitrogen in theheteroaromatic system (preferably pyridinyl) is oxidized. Such compoundscan be obtained in a known manner by reacting a compound of the presentinvention (such as in a pyridinyl group) with H₂O₂ or a peracid in aninert solvent.

Halogen is selected from fluorine, chlorine, bromine and iodine, morepreferably fluorine or chlorine and most preferably fluorine.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients. Isotopically labeledcompounds of this disclosure and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

The disclosure also includes “deuterated analogs” of compounds ofFormula (I) in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds may exhibit increased resistance tometabolism and thus be useful for increasing the half-life of anycompound of Formula (I) when administered to a mammal, e.g. a human.See, for example, Foster in Trends Pharmacol. Sci. 1984:5; 524. Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogens have beenreplaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Furthermore, the compounds of the present invention are partly subjectto tautomerism. For example, if a heteroaromatic group containing anitrogen atom in the ring is substituted with a hydroxy group on thecarbon atom adjacent to the nitrogen atom, the following tautomerism canappear:

A cycloalkyl or heterocycloalkyl group can be connected straight orspirocyclic, e.g. when cyclohexane is substituted with theheterocycloalkyl group oxetane, the following structures are possible:

The term “1,3-orientation” means that on a ring the substituents have atleast one possibility, where 3 atoms are between the two substituentsattached to the ring system, e.g.

The term “1,2-orientation” (ortho) means that on a ring the substituentshave one possibility, where 2 atoms are between the two substituentsattached to the ring system, e.g.

alternatively the residue R can be incorporated in an annelatedadditional cycle. e.g.

It will be appreciated by the skilled person that when lists ofalternative substituents include members which, because of their valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read with the knowledge of the skilledperson to include only those members of the list which are suitable forsubstituting the particular group.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into acompound according to the present invention by a reaction with anenzyme, gastric acid or the like under a physiological condition in theliving body, e.g. by oxidation, reduction, hydrolysis or the like, eachof which is carried out enzymatically. Examples of the prodrug arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated to form, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated. These compounds can be produced from compounds of the presentinvention according to well-known methods. Other examples of the prodrugare compounds (referred to as “ester prodrug” in the application,wherein the carboxylate in a compound of the present invention is, forexample, converted into an alkyl-, aryl-, arylalkylene-, amino-,choline-, acyloxyalkyl-, 1-((alkoxycarbonyl)oxy)-2-alkyl, orlinolenoyl-ester. Exemplary structures for prodrugs of carboxylic acidsare

A ester prodrug can also be formed, when a carboxylic acid forms alactone with a hydroxy group from the molecule. An exemplary example is

The term “—CO₂H or an ester thereof” means that the carboxylic acid andthe alkyl esters are intented, e.g.

The term “glycine conjugate or tauro conjugate thereof” means, that thecarboxylic acid moiety in the molecule is connected with glycine ortaurine, respectively, to form the conjugate (and potentially a prodrug,solvate or pharmaceutically acceptable salt thereof):

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,like e.g. the keto and enol form, are each within the scope of theinvention as well as their mixtures in any ratio. Same applies forstereoisomers, like e.g. enantiomers, cis/trans-isomers, atropisomers,conformers and the like.

If desired, isomers can be separated by methods well known in the art,e.g. by liquid chromatography. Same applies for enantiomers by usinge.g. chiral stationary phases. Additionally, enantiomers may be isolatedby converting them into diastereomers, i.e. coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials. Another way to obtain pure enantiomers from racemic mixtureswould use enantioselective crystallization with chiral counterions.

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In case thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present on thesegroups and can be used according to the invention, for example, asalkali metal salts, alkaline earth metal salts or ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. The compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present andcan be used according to the invention in the form of their additionsalts with inorganic or organic acids. Examples of suitable acidsinclude hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuricacid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid,lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, malic acid, sulfaminic acid,phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid,citric acid, adipic acid, and other acids known to the person skilled inthe art. If the compounds of the present invention simultaneouslycontain acidic and basic groups in the molecule, the invention alsoincludes, in addition to the salt forms mentioned, inner salts orbetaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to the person skilled in the art like,for example, by contacting these with an organic or inorganic acid orbase in a solvent or dispersant, or by anion exchange or cation exchangewith other salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

Further the compounds of the present invention may be present in theform of solvates, such as those which include as solvate water, orpharmaceutically acceptable solvates, such as alcohols, in particularethanol.

Furthermore, the present invention provides pharmaceutical compositionscomprising at least one compound of the present invention, or a prodrugcompound thereof, or a pharmaceutically acceptable salt or solvatethereof as active ingredient together with a pharmaceutically acceptablecarrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing at least one compound of thepresent invention and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients like aprodrug compound or other nuclear receptor modulators.

The compositions are suitable for oral, rectal, topical, parenteral(including subcutaneous, intramuscular, and intravenous), ocular(ophthalmic), pulmonary (nasal or buccal inhalation) or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

The compounds of the present invention act as LXR modulators.

Ligands to nuclear receptors including LXR ligands can either act asagonists, antagonists or inverse agonists. An agonist in this contextmeans a small molecule ligand that binds to the receptor and stimulatesits transcriptional activity as determined by e.g. an increase of mRNAsor proteins that are transcribed under control of an LXR responseelement. Transcriptional activity can also be determined in biochemicalor cellular in vitro assays that employ just the ligand binding domainof LXRα or LXRs but use the interaction with a cofactor (i.e. acorepressor or a coactivator), potentially in conjunction with a genericDNA-binding element such as the Gal4 domain, to monitor agonistic,antagonistic or inverse agonistic activity.

Whereas an agonist by this definition stimulates LXR- or LXR-Gal4-driventranscriptional activity, an antagonist is defined as a small moleculethat binds to LXRs and thereby inhibits transcriptional activation thatwould otherwise occur through an endogenous LXR ligand.

An inverse agonist differs from an antagonist in that it not only bindsto LXRs and inhibits transcriptional activity but in that it activelyshuts down transcription directed by LXR, even in the absence of anendogenous agonist. Whereas it is difficult to differentiate between LXRantagonistic and inverse agonistic activity in vivo, given that thereare always some levels of endogenous LXR agonist present, biochemical orcellular reporter assays can more clearly distinguish between the twoactivities. At a molecular level an inverse agonist does not allow forthe recruitment of a coactivator protein or active parts thereof whereasit should lead to an active recruitment of corepressor proteins areactive parts thereof. An LXR antagonist in this context would be definedas an LXR ligand that neither leads to coactivator nor to corepressorrecruitment but acts just through displacing LXR agonists. Therefore,the use of assays such as the Gal4-mammalian-two-hybrid assay ismandatory in order to differentiate between coactivator orcorepressor-recruiting LXR compounds (Kremoser et al., Drug Discov.Today 2007; 12:860; Gronemeyer et al., Nat. Rev. Drug Discov. 2004;3:950).

Since the boundaries between LXR agonists, LXR antagonists and LXRinverse agonists are not sharp but fluent, the term “LXR modulator” wascoined to encompass all compounds which are not clean LXR agonists butshow a certain degree of corepressor recruitment in conjunction with areduced LXR transcriptional activity. LXR modulators therefore encompassLXR antagonists and LXR inverse agonists and it should be noted thateven a weak LXR agonist can act as an LXR antagonist if it prevents afull agonist from full transcriptional activation.

FIG. 1 illustrates the differences between LXR agonists, antagonists andinverse agonists exemplified by their different capabilities to recruitcoactivators or corepressors.

The compounds are useful for the prophylaxis and/or treatment ofdiseases which are mediated by LXRs. Preferred diseases are alldisorders associated with steatosis, i.e. tissue fat accumulation. Suchdiseases encompass the full spectrum of non-alcoholic fatty liverdisease including non-alcoholic steatohepatitis, liver inflammation andliver fibrosis, furthermore insulin resistance, metabolic syndrome andcardiac steatosis. An LXR modulator based medicine might also be usefulfor the treatment of hepatitis C virus infection or its complicationsand for the prevention of unwanted side-effects of long-termglucocorticoid treatment in diseases such as rheumatoid arthritis,inflammatory bowel disease and asthma.

A different set of applications for LXR modulators might be in thetreatment of cancer. LXR antagonists or inverse agonists might useful tocounteract the so-called Warburg effect which is associated with atransition from normal differentiated cells towards cancer cells (seeLiberti et al., Trends Biochem. Sci. 2016; 41:211; Ward & Thompson,Cancer Cell 2012; 21:297-308). Furthermore, LXR is known to modulatevarious components of the innate and adaptive immune system. Oxysterols,which are known as endogenous LXR agonists were identified as mediatorsof an LXR-dependent immunosuppressive effect found in the tumormicroenvironment (Traversari et al., Eur. J. Immunol. 2014; 44:1896).Therefore, it is reasonable to assume that LXR antagonists or inverseagonists might be capable of stimulating the immune system andantigen-presenting cells, in particular, to elicit an anti-tumor immuneresponse. The latter effects of LXR antagonists or inverse agonistsmight be used for a treatment of late stage cancer, in general, and inparticular for those types of cancerous solid tumors that show a poorimmune response and highly elevated signs of Warburg metabolism.

In more detail, anti-cancer activity of the LXR inverse agonist SR9243was shown to be mediated by interfering with the Warburg effect andlipogenesis in different tumor cells in vitro and SW620 colon tumorcells in athymic mice in vivo (see Flaveny et al. Cancer Cell. 2015;28:42; Steffensen, Cancer Cell 2015; 28:3).

Therefore, LXR modulators (preferably LXR inverse agonists) may byuseful for the treatment of Warburg-dependent cancers.

LXR modulators (preferably LXR inverse agonists) may counteract thediabetogenic effects of glucocorticoids without compromising theanti-inflammatory effects of glucocorticoids and could therefore be usedto prevent unwanted side-effects of long-term glucocorticoid treatmentin diseases such as rheumatoid arthritis, inflammatory bowel disease andasthma (Patel et al. Endocrinology 2017:158:1034).

LXR modulators (preferably LXR inverse agonists) may be useful for thetreatment of hepatitis C virus mediated liver steatosis (seeGarcia-Mediavilla et al. Lab. Invest. 2012; 92:1191).

LXR modulators (preferably LXR inverse agonists) may be useful for thetreatment of viral myocarditis (see Papageorgiou et al. Cardiovasc. Res.2015; 107:78).

LXR modulators (preferably LXR inverse agonists) may be useful for thetreatment of insulin resistance (see Zheng et al. PLoS One 2014;9:e101269).

LXR modulators (preferably LXR inverse agonists) may be useful for thetreatment of familial hypercholesterolemia (see Zhou et al. J. Biol.Chem. 2008; 283:2129).

LXR modulators (preferably LXR inverse agonists) may be useful for thetreatment of hypercholesterolemia in nephrotic syndrome (see Liu &Vazizi in Nephrol. Dial. Transplant. 2014; 29:538).

Experimental Section

The compounds of the present invention can be prepared by a combinationof methods known in the art including the procedures described inSchemes I to V below.

The synthetic route depicted in Scheme I starts with the preparation ofalkynes I-c by Sonogashira couplings. Subsequently, the free amino groupof I-c is reacted with sulfonyl chlorides I-d in the presence of anappropriate base and appropriate solvent to afford alkynesulfonamidesI-e. I-e undergoes cyclization and concomitant reaction with aromatichalides I-f in the presence of appropriate catalyst (e.g. Pd-catalysts),appropriate solvent and temperature to afford compounds of the presentinvention (I). Further manipulation of functional groups present in R¹by standard methods, known to persons skilled in the art (e.g. esterhydrolysis, amide bond formation), can give rise to further compounds ofthe present invention. Alternatively, alkyneamine I-c can be transformedinto alkynetrifluoroacetamides I-g which can also undergo aforementionedcyclization and concomitant reaction with aromatic halides I-f to affordintermediates I-h with an unsubstituted NH. Reaction with sulfonylchlorides I-d in the presence of an appropriate base and appropriatesolvent also affords compounds of Formula (I).

A variation of the routes shown in Scheme I is shown in Scheme II.Alkynesulfonamide I-e is reacted in the presence of NIS to affordiodinated intermediates II-b which can be substrates for Suzukicouplings to afford compounds (I). Alternatively, cyclization ofalkynesulfonamide I-e in the presence of appropriate catalyst (e.g.Pd-catalysts), appropriate solvent and temperature but without thepresence of halides I-f afford 3-unsubstituted intermediates II-d.Reactions with NBS afford brominated intermediates II-e which arelikewise substrates for Suzuki coupling reactions to afford compounds ofFormula (I).

A further variation of the synthetic route depicted in Schemes I and IIis shown in Scheme III. In the presence of B₂Pin₂, appropriate catalyst(e.g. Pd-catalysts), appropriate solvent, additives and temperature,intermediates I-e can undergo cyclization and concomitant formation of3-pinacolyl boronic esters III-b. These can be substrates for Suzukicoupling reactions to afford compounds of the present invention withFormula(I).

In Scheme IV is depicted a synthetic route for the late stageintroduction of the right hand side moieties -L-R¹ to the compounds ofthe present invention. Sonogashira coupling of I-a withbromo-iodo-aromatics IV-a afford bromo-alkyneamines IV-b which can betransformed to sulfonamides IV-c. These can undergo cyclization andconcomitant reaction with aromatic bromides IV-d in the presence ofappropriate catalysts (e.g. Pd-catalysts), appropriate solvent andtemperature to afford advanced intermediates IV-e with a bromosubstituent on ring C. Finally, intermediates IV-e can be used assubstrates for Suzuki couplings to afford compounds of Formula (I).

In Scheme V are summarized the synthetic routes for the preparation ofthe compounds of the present invention starting from the preformedcentral pyrolo-annelated bicyclic aromatic. N-protected 2-pinacolylboronic esters V-a can undergo Suzuki coupling with halides V-b toafford intermediates V-c. After bromination with NBS the 3-bromointermediates V-d are obtained, which, after a second Suzuki coupling,are converted to N-protected advanced intermediates V-s. When startingwith N-protected 3-pinacolyl boronic esters V-a, first Suzuki couplingand then bromination of the 2-position and subsequent second Suzukicoupling affords likewise intermediates V-e. After deprotection andreaction of the free NH with sulfonyl chlorides I-d, in the presence ofan appropriate base and solvent, compounds (are obtained.

Abbreviations

-   Ac acetyl-   ACN acetonitrile-   AIBN azobisisobutyronitrile-   aq. aqueous-   BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)-   B₂Pin₂ 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane-   Boc tert-butyloxycarbonyl-   BPO dibenzoyl peroxide-   m-CPBA meta-chloroperbenzoic acid-   Cy cyclohexyl-   DAST diethylaminosulfur trifluoride-   dba dibenzylideneacetone-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM dichloromethane-   DEA diethanolamine-   DEAD diethyl azodicarboxylate-   DIEA or DIPEA diisopropylethylamine-   DMAP 4-N,N-dimethylaminopyridine-   DMF N,N-dimethylformamide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   EA ethyl acetate-   EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   FCC flash column chromatography on silica gel-   h hour(s)-   HATU O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium    hexafluorophosphate-   HOBt hydroxybenzotriazole-   IBX 2-iodoxybenzoic acid-   LDA lithium diisopropylamide-   LiHMDS lithium bis(trimethylsilyl)amide-   NBS N-bromosuccinimide-   NIS N-iodosuccinimide-   Pin pinacolato (OCMe₂CMe₂O)-   PE petroleum ether-   prep preparative-   sat. saturated (aqueous)-   Sphos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-   TBAF tetra-n-butylammonium fluoride-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic acid anhydride-   THF tetrahydrofuran-   TLC thin layer chromatography-   Tr Trityl-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Preparative Example P1

Methyl 2-(4-bromo-3-chlorophenyl)-2-(dimethylamino)acetate (P1)

To a solution of methyl 2-amino-2-(4-bromo-3-chlorophenyl)acetate (300mg, 1.08 mmol) in MeOH (6 mL) was added CH₂O (37 wt. % in H₂O; 0.5 mL)and HCOOH (2.0 mL). The mixture was stirred at rt for 30 min, thenNaBH(OAc)₃ (572 mg, 2.7 mmol) was added. The mixture was stirred at rtfor 2 h, diluted with EA (150 mL) and washed with water (15 mL), sat.NaHCO₃ (15 mL) and brine (10 mL). The organic layer was dried overNa₂SO₄, filtered, concentrated and purified by prep-TLC (EA:PE=1:4) toafford compound P1 as a colorless oil.

Preparative Example P2

Step 1: 2-((Trimethylsilyl)ethynyl)pyridin-3-amine (P2a)

Pd(PPh₃)₄ (993 mg, 0.86 mmol), CuI (164 mg, 0.86 mmol) and PPh₃ (225 mg,0.86 mmol) were combined in a round-bottom flask, then degassed andrefilled with N₂ three times. To the mixture was added TEA (43 mL),2-bromopyridin-3-amine (1.49 g, 8.59 mmol) and ethynyltrimethylsilane(2.43 mL, 18.0 mmol). The mixture was stirred at 60° C. for 6 h, cooledto rt, filtered through Celite and washed with EA (40 mL). The filtratewas concentrated to give compound P2a as a black solid, which was usedin the next step without further purification.

Step 2: 2-Ethynylpyridin-3-amine (P2)

To a solution of compound P2a (2.16 g, 8.59 mmol) in THF (26 mL) wasadded TBAF (26 mL, 1M in THF, 26 mmol) and the mixture was stirred at rtfor 3 h, concentrated and purified by FCC (EA/PE=1:19 to 1:0) to givecompound P2 as a white solid.

Preparative Example P211 to P2/9

The following Preparative Examples were prepared similar as describedfor Preparative Example P2 using the appropriate building blocks.

# building block structure P2/1

P2/2

P2/3

P2/4

P2/5

P2/6

P2/7

P2/8

P2/9

Preparative Example P3

Step 1: (4-Bromo-2-mercaptophenyl)methanol (P3a)

To a solution of 4-bromo-2-mercaptobenzoic acid (1.5 g, 6.5 mmol) in THF(30 mL) was added BH₃ (13 mL, 1M in THF). This mixture was stirredovernight and quenched with water (30 mL) and diluted with EA (20 mL).The organic layer was separated and the aq. layer was washed with EA(3×20 mL). The combined organic layer was washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated. The yellow solid was usedin the next step without purification.

Step 2: Ethyl 2-((5-bromo-2-(hydroxymethyl)phenyl)thio)acetate (P3b)

To a mixture of compound P3a (436 mg, 2.0 mmol) and ethyl 2-bromoacetate(306 mg, 2.0 mmol) in DMF (10 mL) was added Cs₂CO₃ (2.0 g, 6.0 mmol).The mixture was stirred at rt overnight, diluted with water (100 mL) andextracted with EA (3×30 mL). The combined organic layer was washed withbrine (30 mL), dried over Na₂SO₄, filtered, concentrated and purified byFCC (PE:EA=5:1) to afford compound P3b as a white solid.

Step 3: Ethyl 2-((5-bromo-2-(hydroxymethyl)phenyl)sulfonyl)acetate (P3)

To a stirred solution of compound P3b (290 mg, 1.0 mmol) in DCM (5 mL)at 0° C. was added m-CPBA (610 mg, 3.0 mmol, 85%) and the resultingmixture was stirred at rt for 16 h, diluted with aq. sat. NaHCO₃solution and extracted with EA (3×20 mL). The combined organic layer wasdried over Na₂SO₄, filtered, concentrated and purified by FCC(PE:EA=5:1) to afford compound P3 as a white solid.

Preparative Example P3-1

Step 1: 4-Bromo-2-((2-ethoxy-2-oxoethyl)thio)-6-fluorobenzoic acid(P3-1a)

To a mixture of 4-bromo-2,6-difluorobenzoic acid (10.0 g, 42.4 mmol) andethyl 2-mercapto-acetate (5.10 g, 42.4 mmol) in DMF (100 mL) was addedCs₂CO₃ (41.5 g, 127 mmol) and the mixture was stirred at 80° C.overnight, diluted with water (1 L) and adjusted to pH=3 with 2M HCl andextracted with EA (3×300 mL). The combined organic layer was washed withbrine (300 mL), dried over Na₂SO₄, filtered, concentrated and purifiedby FCC (PE:EA=1:1) to give compound P3-1a as a yellow oil.

Step 2: Ethyl 2-((5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)thio)acetate(P3-1b)

To the solution of compound P3-1a (4.10 g, 12.2 mmol) in THF (40 mL) wasadded B₂H6 (24.4 mL, 1M in THF). This mixture was stirred at 70° C.overnight, quenched with water (100 mL) and extracted with EA (4×40 mL).The combined organic layer was washed with brine (50 mL), dried overNa₂SO₄, filtered, concentrated and purified by FCC (PE:EA=5:1) to givecompound P3-1b as a white solid.

Step 3: Ethyl2-((5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)sulfonyl)acetate (P3-1)

To a stirred solution of compound P3-1b (1.00 g, 3.40 mmol) in DCM (30mL) at 0° C. was added m-CPBA (1.80 g, 10.2 mmol, 85%) and the mixturewas stirred at rt for 16 h, diluted with aq. sat. NaHCO₃ solution andextracted with EA (3×20 mL). The combined organic layer was dried overNa₂SO₄, concentrated and purified by FCC (PE:EA=5:1) to give compoundP3-1 as a white solid.

Preparative Example P4

Methyl 2-(3-bromophenyl)-2-methylcyclopropane-1-carboxylate (P4)

To a solution of compound P16 (1.00 g, 3.92 mmol) in DMF (15 mL) wasadded Mel (1.11 g, 7.84 mmol) and K₂CO₃ (1.35 g, 9.80 mmol). The mixturewas stirred for 2 h at 50° C., cooled, diluted with EA (100 mL) andwashed with water (3×20 mL) and brine (20 mL), dried over Na₂SO₄,filtered, concentrated and purified by prep-TLC (EA:PE=1:6) to givecompound P4 as a yellow oil.

Preparative Example P5

Methyl 3′-bromo-2-chloro-[1,1′-biphenyl]-4-carboxylate (P5)

To a solution of methyl3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (47.7g, 161 mmol) in dioxane (300 mL) was added 1-bromo-3-iodobenzene (50.0g, 177 mmol), Na₂CO₃ (35.7 g, 337 mmol) and Pd(PPh₃)₄ (11.7 g, 10.1mmol) under N₂. The mixture was stirred at 90° C. overnight under N₂,cooled, filtered, concentrated and purified by FCC (EA:PE=1:50) to givecompound P5 as a white solid.

Preparative Example P5/1 to P5/3

The following Preparative Examples were prepared similar as describedfor Preparative Example P5 using the appropriate building blocks.

# building block(s) structure P5/1

P5/2

P5/3

Preparative Example P6

4-(Methyl-d3)benzenesulfonyl chloride-2.3.5.6-d4 (P6)

To a solution of toluene-d8 (1.00 g, 10.0 mmol) in DCM (10 mL) was addedCISO₃H (5 mL) and the mixture was stirred at rt for 2 h, poured intowater (100 mL) and extracted with DCM (100 mL). The organic layer wasconcentrated to give compound P6 as a white solid.

Preparative Example P7

tert-Butyl 2-(3-bromo-4-cyanophenoxy)acetate (P7)

A mixture of 2-(3-bromo-4-cyanophenoxy)acetic acid (200 mg 0.78 mmol),Boc₂O (204 mg 0.94 mmol), DMAP (10 mg, 80 μmol) and pyridine (0.4 mL) intert-BuOH (10 mL) was stirred at rt overnight, concentrated and purifiedby FCC (PE:EA=50:1) to give compound P7 as a yellow oil.

Preparative Example P7/1

The following Preparative Example was prepared similar as described forPreparative Example P7 using the appropriate building block.

# building block structure P7/1

Preparative Example P8

Methyl5-chloro-2-fluoro-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)benzoate(P8)

To a solution of methyl 4-bromo-5-chloro-2-fluorobenzoate (2.66 g, 10.0mmol) in dioxane (30 mL) was added B₂Pin₂ (2.79 g, 11.0 mmol), KOAc(2.45 g, 25.0 mmol) and Pd(dppf)Cl₂ (260 mg) under N₂. The mixture wasstirred at 80° C. overnight under N₂, diluted with water (50 mL) andextracted with EA (3×50 mL). The combined organic layer was washed withbrine, dried over Na₂SO₄, filtered, concentrated and purified by FCC(EA:PE=1:40) to give compound P8 as a white solid.

Preparative Example P9

Methyl 4-(3-bromophenyl)butanoate (P9)

To a solution of 4-(3-bromophenyl)butanoic acid (500 mg, 2.06 mmol) inDMF (50 mL) was added K₂CO₃ (569 mg, 4.11 mmol) and CH₃ (438 mg, 3.09mmol). The mixture was stirred for 2 h at rt. Insoluble salts werefiltered off and washed with EA. The combined organic layer was washedwith water (3×50 mL), brine (2×50 mL), dried over Na₂SO₄ and filtered.The solvents were removed under reduced pressure to afford compound P9as a yellow solid, which was used in the next step without furtherpurification.

Preparative Example P10

Methyl 2-(3-bromophenoxy)acetate (P10)

To a solution of 3-bromophenol (1.72 g, 10.0 mmol) andmethyl-bromoacetate (1.01 mL, 11.0 mmol) in ACN (60 mL) was added K₂CO₃(2.07 g, 15.0 mmol) and the mixture was stirred at 50° C. overnight.After insoluble salts are filtered off and washed with ACN, the solventis removed under reduced pressure and the remainder is taken up in EAand washed subsequently with water and brine. The organic layer is driedover Na₂SO₄, filtered and concentrated to give compound P10 as acolorless semi-solid.

Preparative Examples P10/1

The following Example was prepared similar as described for PreparativeExample P10 using the appropriate building blocks.

# building block structure P10/1

Preparative Example P11

Methyl 3-((6-bromopyridin-2-yl)oxy)propanoate (P11)

To a solution of 6-bromopyridin-2(1H)-one (800 mg, 4.59 mmol) and PPh₃(2.39 g, 9.19 mmol) in dry THE (30 mL) under N₂ was added DEAD (1.20 g,6.89 mmol) and methyl 3-hydroxypropanoate (479 mg, 4.59 mmol). Themixture was stirred at rt overnight, quenched with sat. NH₄Cl (60 mL)and extracted with EA (2×30 mL). The combined organic layer was washedwith brine (2×30 mL), dried over Na₂SO₄, concentrated and purified byprep-TLC (EA:PE=1:4) to give compound P11 as a white solid.

Preparative Example P12

Methyl 1-(3-bromophenyl)azetidine-3-carboxylate (P12)

To a solution of 1-bromo-3-iodobenzene (500 mg, 1.77 mmol) in dioxane (8mL) was added methyl azetidine-3-carboxylate hydrochloride (295 mg, 1.94mol), Pd₂(dba)₃ (35 mg, 40 μmol), XPhos (17 mg, 40 μmol) and Na₂CO₃ (375mg, 3.53 mmol). The mixture was stirred at 100° C. overnight, cooled tort, filtered, concentrated and purified by prep-TLC (PE:EA=2:1) to givecompound P12 as a yellow oil.

Preparative Example P12/1

The following Preparative Example was prepared similar as described forPreparative Example P12 using the appropriate building block.

# building block structure P12/1

Preparative Example P13

Methyl 1-(3-bromophenyl)-3-methylazetidine-3-carboxylate (P13)

To a solution of 1-bromo-3-iodobenzene (500 mg, 1.77 mmol) in dioxane(15 mL) was added methyl 3-methylazetidine-3-carboxylate hydrochloride(293 mg, 1.77 mmol), Pd₂(dba)₃ (32 mg, 35 μmol), Xantphos (20 mg, 35μmol) and Cs₂CO₃ (1.35 g, 3.54 mmol). The mixture was stirred at 100° C.overnight under N₂, cooled to rt, diluted with water (150 mL) andextracted with EA (3×200 mL). The combined organic layer was washed withbrine (2×50 mL), dried over Na₂SO₄, concentrated and purified by FCC(EA:PE=1:5) to afford compound P13 as a yellow oil.

Preparative Example P13/1 to P13/4

The following Preparative Examples were prepared similar as describedfor Preparative Example P13 using the appropriate building blocks.

# building blocks structure P13/1

P13/2

P13/3

P13/4

Preparative Example P14

Methyl 1-(6-bromopyridin-2-yl)azetidine-3-carboxylate (P14)

To a solution of 2,6-dibromopyridine (500 mg, 2.11 mmol) in DMF (20 mL)was added methyl azetidine-3-carboxylate hydrochloride (384 mg, 2.53mmol) and K₂CO₃ (729 mg, 5.28 mmol) and the mixture was stirredovernight at 80° C. After cooling to rt insoluble salts were filteredoff and washed with EA. The combined organic solvents were washed withwater (3×50 mL), brine (2×50 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (PE:EA=4:1) to affordcompound P14 as a yellow oil.

Preparative Example P15

Step 1: 3-(3-Bromophenyl)-3-hydroxycyclobutane-1-carboxylic Acid (P15a)

To a solution of 1-bromo-3-iodobenzene (2.82 g, 10.0 mmol) and3-oxocyclobutane-1-carboxylic acid (1.14 g, 10.0 mmol) in THF (30 mL) at−78° C. was added n-BuLi (8 mL, 20 mmol, 2.5 M in THF) and the mixturewas stirred at −78° C. for 4 h, quenched with NH₄Cl (50 mL), neutralizedwith 1N aq. HCl and extracted with EA (3×). The combined organic layerwas washed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by FCC (EA:PE=1:1) to give compound P15a as a colorless oil.

Step 2: Methyl 3-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylate(P15b)

To a solution of compound P15a (1.35 g, 5.00 mmol) in DMF (20 mL) wasadded K₂CO₃ (1.38 g, 10.0 mmol) and CH₃ (710 mg, 5.00 mmol) and themixture was stirred at rt for 2 h. Water was added (200 mL) and themixture was extracted with EA. The combined EA extracts were washed withbrine, dried over Na₂SO₄ and filtered. The solvent was removed underreduced pressure and the residue was purified by FCC (EA:PE=1:10) togive compound P15b as a colorless oil.

Step 3: Methyl 3-(3-bromophenyl)cyclobutane-1-carboxylate (P15)

To a solution of compound P15b (1.10 g, 3.90 mmol) in TFA (20 mL) at 0°C. was added triethylsilane (680 mg, 5.85 mmol) and the mixture wasstirred for 2 h. Water was added to the mixture (200 mL) and the mixtureextracted with EA. The solvent was removed under reduced pressure andthe residue was purified by FCC (EA:PE=1:10) to give compound P15 as acolorless oil.

Preparative Example P16

Step 1: Methyl (E)-3-(3-bromophenyl)acrylate (P16a)

(E)-3-(3-Bromophenyl)acrylic acid (3.00 g, 13.2 mmol) was dissolved inDMF (50 mL), Mel (3.75 g, 26.4 mmol) and K₂CO₃ (2.74 g, 19.8 mmol) wereadded and the mixture was stirred for 2 h at rt. After insoluble saltswere filtered and washed with EA, the solvent was washed with water(3×50 mL), brine (2×50 mL), dried over Na₂SO₄, filtered and concentratedto give compound P16a as a yellow solid which was used in the next stepwithout any purification.

Step 2: rac-Methyl (1R,2R)-2-(3-bromophenyl)cyclopropane-1-carboxylate(P16)

Under argon, NaH (60%, 680 mg, 17.0 mmol) was initially charged in DMSO(30 mL) and trimethylsulphoxonium iodide (3.74 g, 17.0 mmol) was addedin one portion at rt. After the evolution of gas had ceased, compoundP16a (3.15 g, 13.1 mmol), dissolved in DMSO (10 mL), was slowly addeddrop-wise. After stirring overnight at 50° C., the mixture waspartitioned between EA and water. The aq. layer was extracted with EA.The combined organic layer was dried over Na₂SO₄, filtered, concentratedand purified by FCC (EA:PE=1:20) to give compound P16 as a colorlessoil.

Preparative Example P16/1 to P16/2

The following Preparative Examples were prepared similar as describedfor Preparative Example P16 using the appropriate building blocks.

# building block structure chemical name P16/1

rac-methyl (1R,2R)-2-(5-bromothiophen-2- yl)cyclopropane-1-carboxylateP16/2

rac-methyl (1R,2R)-2-(3-bromo-5- chlorophenyl)cyclopropane-1-carboxylate

Preparative Example P17

Methyl 3′-bromo-[1,1′-biphenyl]-3-carboxylate (P17)

To a solution of (3-bromophenyl)boronic acid (1.50 g, 7.47 mmol) indioxane (30 mL) was added methyl 3-bromobenzoate (1.93 g, 8.96 mmol),Pd(PPh₃)₄ (173 mg, 0.15 mmol) and Na₂CO₃ (1.58 g, 14.9 mmol). Themixture was stirred at 100° C. overnight. After cooling to rt thereaction was filtered, concentrated and purified by FCC to give compoundP17 as a yellow oil.

Preparative Examples P17/1 to P17/4

The following Examples were prepared similar as described forPreparative Example P17 using the appropriate building blocks.

# building block structure P17/1

P17/2

P17/3

P17/4

Preparative Example P18

Step 1: Methyl3′-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-4-carboxylate (P18a)

Pd(PPh₃)₄ (1.98 g, 1.72 mmol), CuI (327 mg, 1.72 mmol) and PPh₃ (450 mg,1.72 mmol) were combined in a round-bottom flask and the flask wasdegassed and refilled with N₂ three times. TEA (86 mL), methyl3′-bromo-[1,1′-biphenyl]-4-carboxylate (P/2, 5.00 g, 17.2 mmol) andethynyltrimethylsilane (4.86 mL, 36.1 mmol) were added and the mixturewas stirred at 60° C. for 6 h. After filtration through kieselgur thefiltrate was concentrated under reduced pressure to give compound P18aas a black solid, which was used in the next step without furtherpurification.

Step 2: Methyl 3′-ethynyl)-[1,1′-biphenyl]-4-carboxylate (P18)

To a solution of compound P18a (6.21 g, 17.2 mmol) in THF (25 mL) wasadded TBAF (25 mL, 1M in THF) and the mixture was stirred at rt for 3 h.After concentration under reduced pressure the residue was purified byFCC (EA:PE=1:20) to give compound P18 as a white solid.

Preparative Example P19

Step 1: 3-Bromofuran-2-carboxamide (P19a)

To a solution of 3-bromofuran-2-carboxylic acid (1.00 g, 5.24 mmol) inDMF (10 mL) was added HATU (2.98 g, 7.85 mmol) and DIPEA (1.69 g, 13.1mmol) and the mixture was stirred at rt for 1 h. NH₄Cl (333 mg, 6.29mmol) was added and stirring was continued overnight. Water (30 mL) wasadded, and the mixture was extracted with EA (3×30 mL). The combinedorganic layer was dried over Na₂SO₄, concentrated and purified by FCC togive compound P19a as a yellow solid.

Step 2: 3-Bromofuran-2-carbonitrile (P19)

To a solution of compound 19a (906 mg, 4.77 mmol) in DCM (10 mL) at 0°C. was added TFAA (2.50 g, 11.9 mmol) and the mixture was stirred for 2h, diluted with water (30 mL) and extracted with DCM (3×30 mL). Thecombined organic layer was dried over Na₂SO₄, concentrated and purifiedby FCC (EA:PE=1:20) to give compound P19 as a white solid.

Preparative Example P20

2-Bromo-4-fluoro-6-methoxyaniline (P20)

NBS (12.4 g, 69.4 mmol) was added to a solution of4-fluoro-2-methoxyaniline (8.90 g, 63.1 mmol) in dry DCM (217 mL) at−78° C. and the mixture was stirred at −78° C. for 2 h, then allowed towarm to 0° C. and stirred for 2 h. The solvent was removed in vacuum andthe resulting residue was purified by FCC (EA:PE=1:10) to give compoundP20 as a yellow oil.

Preparative Example P21

Step 1:2-(4-Bromophenyl)-2-(trimethylsilyl)oxy)propanenitrile (P21a)

Trimethylsilyl cyanide (4.96 g, 50.0 mmol) and zinc iodide (50 mg) wereadded to 1-(4-bromophenyl)ethan-1-one (5.00 g, 50.0 mmol) in DCM (200mL). This mixture was stirred for 5 h at rt. The mixture was washed withwater (2×20 mL) and brine (20 mL). The organic layer was dried overNa₂SO₄ and concentrated to afford crude compound P21a, which was used inthe next step without any purification.

Step 2: 2-(4-Bromophenyl)-2-hydroxypropanoic Acid (P21b)

To the solution of compound P21a (12.2 g, 40.9 mmol) in AcOH (50 mL) wasadded conc. HCl (50 mL). The mixture was stirred overnight at rt andheated at 100° C. for 2 h. The solvent was removed under reducedpressure. H₂O was added and the mixture was extracted with EA (3×200mL). The organic layer was dried over Na₂SO₄ and concentrated to givecrude compound P21b as a yellow oil, which was used in the next stepwithout any purification.

Step 3: Methyl 2-(4-bromophenyl)-2-hydroxypropanoate (P21c)

To a solution of compound P21b (6.50 g, 26.5 mmol) in MeOH (60 mL) wasadded conc. H₂SO₄ (3 mL). The mixture was stirred overnight at rt. Thesolvent was removed under reduced pressure, dissolved in EA (300 mL) andwashed with H₂O (30 mL) and sat. NaHCO₃ (30 mL). The organic layer wasdried over Na₂SO₄, concentrated and purified by FCC (EA:PE=1:2) to givecompound P21c as a colorless oil.

Step 4: Methyl2-hydroxy-2-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)phenyl)propanoate(P21)

To a solution of compound P21c (200 mg, 0.77 mmol) in dioxane (10 mL)was added B₂Pin₂ (209 mg, 0.93 mmol), KOAc (151 mg, 1.54 mmol) andPd(dppf)Cl₂ (56 mg, 0.08 mmol). The mixture was stirred at 100° C.overnight under N₂. After cooling to rt, the mixture was filtered andthe solvent was removed under reduced pressure. The residue was purifiedby prep-TLC (EA:PE=1:1) to afford compound P21 as a white solid.

Preparative Examples P21/1

The following Example was prepared similar as described for PreparativeExample P21 using the appropriate building block.

# building block structure P21/1

Preparative Example P22 (mixture of 1- and 2-trityl Isomer)

Step 1: 5-(4-Bromo-3-chlorophenyl)-1H-tetrazole (P22a)

To a solution of 4-bromo-3-chlorobenzonitrile (500 mg, 2.33 mmol) in DMF(10 mL) was added NaN₃ (1.50 g, 23.3 mmol) and NH₄Cl (1.20 g, 23.3mmol). The mixture was stirred at 100° C. under N₂ overnight. Then DCM(100 mL) was added and the mixture was washed with brine (30 mL). Theorganic layer was dried over Na₂SO₄, concentrated and purified by FCC(EA:PE=1:3) to give compound P22a as a white solid.

Step 2: 5-(4-Bromo-3-chlorophenyl)-1-trityl-1H-tetrazole (P22), (mixtureof 1- and 2-trityl Isomers)

To a solution of compound P22a (350 mg, 1.36 mmol) in DCM (50 mL) wasadded triphenylmethyl chloride (556 mg, 2.00 mmol) and TEA (202 mg, 2.00mmol). The mixture was stirred at rt for 12 h. Then DCM (50 mL) wasadded and the mixture was washed with brine (30 mL). The organic layerwas dried over Na₂SO₄, concentrated and purified by FCC (EA:PE=1:7) toafford compound P22 as a white solid.

Preparative Example P23 (Mixture of 1- and 2-trityl Isomers)

Step 1:N-((3-Bromophenyl)(methyl)(oxo)-λ⁶-sulfaneylidene)-2,2,2-trifluoroacetamide(P23a)

To a solution of 1-bromo-3-(methylsulfinyl)benzene (950 mg, 4.38 mmol)in DCM (10 mL) was added MgO (697 mg, 17.4 mmol),2,2,2-trifluoroacetamide (742 mg, 6.57 mmol), Rh₂(OAc)₄ (100 mg) and(diacetoxy)iodobenzene (2.82 g, 8.76 mmol). The mixture was stirred at40° C. overnight and filtered through a pad of Celite. The solvent wasremoved under reduced pressure and the crude product was purified by FCC(PE:EA=1:2) to give compound P23a as a white solid.

Step 2: (3-Bromophenyl)(imino)(methyl)-λ⁶-sulfanone (P23b)

To a stirred solution of compound P23a (680 mg, 2.07 mmol) in MeOH (5mL) was added K₂CO₃ (713 mg, 5.17 mmol) and stirring was continued at rtfor 1 h. Then water was added and the mixture was extracted with EA(3×20 mL). The combined organic layer was washed with brine (20 mL),dried over Na₂SO₄ and concentrated to give compound P23b as a whitesolid.

Step 3: N-((3-Bromphenyl)(methyl(oxo)-λ⁶-sulfaneylidene)cyanamide (P23c)

To a solution of compound P23b (430 mg, 1.86 mmol) in DCM (5 mL) wasadded cyanic bromide (235 mg, 2.24 mmol) and TEA (376 mg, 3.72 mmol).The mixture was stirred at rt for 3 h, diluted with water and extractedwith EA (3×20 mL). The combined organic layer was washed with sat. aq.NaHCO₃ (20 mL), dried over Na₂SO₄ and concentrated to give compound P23cas a yellow solid.

Step 4: ((1H-Tetrazol-5-yl)imino)(3-bromophenyl)(methyl)-λ⁶-sulfanone(P23d)

To a stirred solution of compound P23c (420 mg, 1.63 mmol) in DMF (5 mL)was added NaN₃ (1.06 g, 16.3 mmol) and NH₄Cl (864 mg, 16.3 mmol). Themixture was stirred and heated to 100° C. overnight. After cooling tort, water was added and the mixture was extracted with EA (3×20 mL). Thecombined organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by prep-TLC (PE:EA=1:1) to give compound P23d as a white solid.

Step 5:(3-Bromophenyl)(methyl)₁-trityl-1H-tetrazol-5-yl)imino)-λ⁶-sulfanone(P23) (Mixture of 1- and 2-trityl Isomer)

To a stirred solution of compound P23d (350 mg, 1.16 mmol) in DCM (20mL) was added trityl chloride (388 mg, 1.39 mmol) and TEA (0.3 mL, 2.3mmol). Stirring was continued at rt overnight. Then water was added andthe mixture was extracted with DCM (3×50 mL). The combined organic layerwas washed with brine (20 mL), dried over Na₂SO₄, concentrated andpurified by FCC (EA:PE=1:3) to give compound P23 as a white solid.

Preparative Example P24

rel-Methyl (1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-carboxylateHydrochloride (P24)

rel-(1R,3r,5S)-8-(tert-Butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid (500 mg, 1.96 mmol) was dissolved in HCl in MeOH (20 mL). Thesolution was stirred at rt for 5 h. The solvent was removed underreduced pressure to afford compound P24 as a white solid.

Preparative Example P25

Step 1: (4-Bromo-2-(methylsulfonyl)phenyl)methanol (P25a)

To a solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (3.00 g, 10.2mmol) in MeOH (20 mL) was added LiBH₄ (4.00 g, 100 mmol) slowly at 0° C.The mixture was stirred at 80° C. overnight. Water (40 mL) was addedslowly under cooling with an ice bath and the mixture was extracted withEA (3×30 mL). The combined organic layer was washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive compound P25a as a pale yellow solid, which was directly used inthe next step.

Step 2: 2-(4-Bromo-2-(methylsulfonyl)phenyl)acetonitrile P25b)

To a solution of cyanic bromide (712 mg, 6.70 mmol) and PPh₃ (1.76 g,6.70 mmol) in DCM (30 mL) was added a solution of compound P25a (1.50 g,5.60 mmol) in DCM (50 mL). The mixture was stirred at 15° C. for 1 h,then DBU (1.10 g, 6.70 mmol) was added at 0° C. The resulting mixturewas stirred at 0-15° C. for another 16 h. The solvent was concentratedin vacuum. The residue was purified by FCC (PE:EA=4:1) to give compoundP25b as a yellow solid.

Step 3: 2-(4-Bromo-2-(methylsulfonyl)phenyl)-2-methylpropanenitrile(P25c)

To a solution of compound P25b (200 mg, 1.10 mmol) in THF (20 mL) wereadded potassium tert-butoxide (502 mg, 4.40 mmol) and iodomethane (624mg, 4.40 mmol) at −78° C. The mixture was warmed to −20° C. and stirredovernight, diluted with aq. NH₄Cl (30 mL) and extracted with EA (3×30mL). The combined organic layer was washed with brine (100 mL), driedover Na₂SO₄, filtered, concentrated and purified by FCC (PE:EA=100:8) togive compound P25c as a yellow solid.

Step 4: 2-(4-Bromo-2-(methylsulfonyl)phenyl)-2-methylpropanoic Acid(P25)

To a solution of compound P25c (850 mg, 2.80 mmol) in EtOH (5 mL) andH₂O (5 mL) was added KOH (1.20 g, 22.4 mmol). The mixture was stirred at80° C. for 2 d. The pH was adjusted to ca. 5 by addition of 1N aq. HCland the mixture was extracted with DCM/MeOH (10/1, 3×40 mL). Thecombined organic layer was washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give compound P25 as a yellowsolid.

Preparative Example P26

4-Bromo-3-(trifluoromethyl)-1-trityl-1H-pyrazole (P26)

To a stirred solution of 4-bromo-5-(trifluoromethyl)-1H-pyrazole (428mg, 2.00 mmol) in DCM (10 mL) was added TEA (606 mg, 6.00 mmol) and(chloromethanetriyl)tribenzene (1.11 g, 4.00 mmol) and stirring wascontinued at rt overnight. Then the solvent was removed and H₂O (50 mL)was added and the mixture was extracted with EA (3×50 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by FCC (PE:EA=5:1) to give compound P26 as awhite solid.

Preparative Example P27

Step 1: tert-Butyl 3-(2-bromophenyl)-3-hydroxyazetidine-1-carboxylate(P27a)

To a solution of 1-bromo-2-iodobenzene (8.43 g, 30.0 mmol) in THF (50mL) at −78° C. was slowly added i-PrMgBr in THE (0.90M, 33 mL, 30.0mmol). After stirring for 2 h, a solution of tert-butyl3-oxoazetidine-1-carboxylate (3.20 g, 19.0 mmol) in THF (20 mL) wasadded dropwise to the mixture at −78° C. The mixture was stirred at rtfor 3 h, diluted with sat. aq. NH₄Cl and extracted with EA. The organiclayer was washed with water and brine, dried over Na₂SO₄, concentratedand purified by FCC (PE:DCM=2:1) to afford compound P27a as a whitesolid.

Step 2: tert-Butyl 3-(2-bromophenyl)-3-fluoroazetidine-1-carboxylate(P27)

To a stirred solution of compound P27a (4.30 g, 13.1 mmol) in DCM (50mL) at 0° C. was slowly added DAST (4.20 g, 26.2 mmol). After stirringfor 4 h, the mixture was poured into water and extracted with EA. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrated andpurified by FCC (PE:DCM=3:1) to give compound P27 as a colorless oil.

Preparative Example P28

Step 1: 3-(3-Bromothiophen-2-yl)oxetan-3-ol (P28a)

To a suspension of 3-bromothiophene (13.0 g, 80.2 mmol) in THF (20 mL)was added LDA (48.0 mL, 2.0M in THF, 96.0 mmol) under N₂ at −60° C. Themixture was stirred at −60° C. for 45 min. Then oxetan-3-one (8.70 g,121 mmol) was added and stirring was continued for 30 min at −60° C.Water was added slowly and the mixture was extracted with EA (3×). Thecombined organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by FCC (PE:EA=10:1 to 5:1) to give compound P28a as a brownoil.

Step 2: 3-(3-Bromothiophen-2-yl)oxetane (P28)

To a mixture of compound P28a (17.0 g, 72.6 mmol) in DCM (120 mL) wasadded BF₃-Et₂O (18.5 mL, 146 mmol) at 0° C. under N₂. The mixture wasstirred at 0° C. for 30 min. Then triethylsilane (35.0 mL, 220 mmol) wasadded and the mixture was stirred at 0° C. for 30 min. Furthertriethylsilane (35.0 mL, 220 mmol) was added and the mixture was stirredat 0° C. for 30 min. A third portion of triethylsilane (35.0 ml, 220mmol) was added and stirring was continued at 0° C. 30 min. The mixturewas added to a solution aq. NaOH (10%, 200 g) under cooling with an icebath and extracted with EA (3×). The combined organic layer was driedover Na₂SO₄, filtered, concentrated and purified by FCC (PE/DCM=10:1 to3:1) to give compound P28 as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ:7.23 (d, J=5.2 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 5.08-5.04 (m, 2H),4.80-4.77 (m 2H), 4.67-4.59 (m, 1H).

Preparative Example P29

Step 1: 2-Bromocyclohex-1-ene-1-carboxamide (P29a)

To a solution of 2-bromocyclohex-1-ene-1-carboxylic acid (1.20 g, 5.88mmol) in DCM (20 mL) was added HATU (3.35 g, 8.82 mmol), DIPEA (2.16 g,16.7 mmol) and NH₄Cl (3.20 g, 58.9 mmol). The mixture was stirred at rtfor 24 h, filtered, concentrated and purified by FCC (PE:EA=1:1) to givecompound P29a as a colorless oil.

Step 2: 2-Bromocyclohex-1-ene-1-carbonitrile (P29)

To a solution of compound P29a (510 mg, 2.51 mmol) in DCM (20 mL) wasadded TFAA (1.05 g, 5.02 mmol) at 0° C. The mixture was stirred at rtfor 12 h, poured into water (50 mL) and extracted with DCM (3×20 mL).The combined the organic layer was washed with brine (30 mL), dried overNa₂SO₄, filtered, concentrated and purified by FCC (PE:EA=2:1) to givecompound P29 as a white solid.

Preparative Example P30

Step 1: Methyl2-chloro-3′-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-4-carboxylate P30a

Pd(PPh₃)₄ (553 mg, 0.48 mmol), CuI (93 mg, 0.48 mmol) and PPh₃ (126 mg,0.48 mmol) were combined in a round-bottom flask, then degassed andrefilled with N₂ three times. To the mixture was added TEA (45 mL),compound P5 (2.00 g, 6.10 mmol), ethynyltrimethylsilane (786 mg, 10.2mmol) and then the mixture was stirred at 60° C. for 6 h, cooled,filtered through kieseguhr and washed with EA (40 mL). The filtrate wasconcentrated and purified by FCC (PE:EA=20:1) to give compound P30a as ayellow solid.

Step 2: Methyl 2-chloro-3′-ethynyl-[1,1′-biphenyl]-4-carboxylate (P30)

To a solution of compound P30a (2.05 g, 5.89 mmol) in MeOH (5 mL) wasadded K₂CO₃ (778 mg, 7.07 mmol) and the mixture was stirred at rt for 30min, poured into ice water (50 mL) and extracted with DCM (2×50 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto give compound P30 as a yellow solid.

Preparative Example P31

1-(2-Chloropyridin-3-yl)azetidin-3-ol (P31)

To a solution of 2-chloro-3-iodopyridine (1.20 g, 5.00 mmol) in toluene(20 mL) was added azetidin-3-ol hydrochloride (1.09 g, 10.0 mmol),Cs₂CO₃ (6.52 g, 20.0 mmol), BINAP (311 mg, 0.50 mmol) and Pd₂(dba)₃ (200mg) under N₂. The mixture was stirred at 110° C. overnight under N₂.After cooling to rt the mixture was filtered and the solvent was removedunder reduced pressure. The residue was purified by FCC (EA:PE=1:3) togive compound P31 as a yellow solid.

Preparative Example P32

Ethyl 2-(4-bromophenyl)-2-hydroxypropanoate (P32)

To a solution of ethyl 2-(4-bromophenyl)-2-oxoacetate (512 mg, 2.00mmol) in THF (30 mL) was added MeMgBr (2 mL, 1M in THF) at 0° C. Themixture was stirred at 0° C. for 1 h, diluted with water (50 mL) andextracted with EA (3×50 mL). The combined organic layer was washed withbrine, dried over Na₂SO₄, filtered, concentrated and purified by FCC(PE:EA=5:1) to give compound P32 as a white solid.

Preparative Examples P32/1

The following Preparative Example was prepared similar as described forPreparative Example P32 using the appropriate building block.

# building block structure P32/1

Preparative Example P33

4-Bromo-3-chlorobenzenesulfonic Acid (P31)

A solution of 4-bromo-3-chlorobenzenesulfonyl chloride (576 mg, 2.00mmol) in H₂O (30 mL) was stirred at 100° C. for 16 h and concentrated togive compound P33 as a white solid.

Preparative Example P34

Step 1: N-((4-Bromo-3-chlorophenyl)sulfonyl)acetamide (P34a)

4-Bromo-3-chlorobenzenesulfonamide (1.5 g, 5.5 mmol) was dissolved inpyridine (5 mL). Then DMAP (22 mg, 0.18 mmol) and Ac₂O (1.1 mL, 12 mmol)were added and the mixture was stirred for 3 h at rt, diluted with EAand washed with aq. NH₄Cl solution (3×) and water. The organic layer wasdried over Na₂SO₄ and concentrated. The resulting oil was trituratedwith PE and the precipitate was collected by filtration to affordcompound P34a as a white solid.

Step 2:N-((3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)acetamide(P34)

To a solution of compound P34a (310 mg, 1.00 mmol) in dioxane (5 mL) wasadded B₂Pin₂ (381 mg, 1.50 mmol), KOAc (276 mg, 2.00 mmol) andPd(dppf)Cl₂ (120 mg). The mixture was stirred under N₂ at 90° C. for 8h, cooled, filtrated, concentrated and purified by FCC (PE:EA=5:1) togive compound P34 as a yellow solid.

Preparative Example P35

Step 1: 4-Bromopyridine-3,5-dicarboxylic acid (P35a)

To a solution of 4-bromo-3,5-dimethylpyridine (1.24 g, 6.72 mmol) inwater (15 mL) was added KMnO₄ (1.59 g, 10.1 mmol) and the mixture wasstirred at 100° C. for 1 h. Then an additional amount of KMnO₄ (1.59 g,10.1 mmol) in water (15 mL) was added and stirring at 100° C. wascontinued for 2 h. Then the mixture was filtered and the solventconcentrated to about 5 mL, adjusted to pH=2 with conc. HCl andconcentrated to give compound P35a as a white solid.

Step 2: 4-Chloropyridine-3,5-dicarboxamide (P35b)

To a solution of compound P35a (1.30 g, 5.30 mmol) in DCM (15 mL) wasadded SOCl₂ (1.5 mL) and DMF (3 drops). The mixture was stirred at 45°C. for 2 h, concentrated and redissolved in dioxane (5 mL). NH₃.H₂O (20mL) was added dropwise to the solution at 0° C. and then concentrated togive compound P35b as a yellow solid.

Step 3: 4-Chloropyridine-3,5-dicarbonitrile (P35)

To a solution of compound P35b (188 mg, 0.94 mmol) in DMF (5 mL) wasadded POCl₃ (1 mL) and the mixture was stirred at rt overnight, dilutedwith water (30 mL) and extracted with EA (3×50 mL). The combined organiclayer was washed with aq. NaHCO₃ (30 mL), concentrated and purified byFCC (PE:EA=5:1) to give compound P35 as a white solid.

General remarks: A “C” before the example number means that it is acomparative example while a “P” before the example number means that theexample contains a protection group. These examples are not fallingwithin the scope of the claims.

Example 1

Step 1: 2-((3-Bromophenyl)ethynyl)-4-fluoroaniline (1a)

To a solution of 1-bromo-3-iodobenzene (5.00 g, 17.7 mmol) in Et₃N (50mL) was added Pd(PPh₃)₄ (1.22 g, 1.06 mmol), CuI (269 mg, 1.41 mmol),PPh₃ (278 mg, 1.06 mmol) and 2-ethynyl-4-fluoroaniline (2.86 g, 21.2mmol). The mixture was stirred at 60° C. under N₂ for 4 h, cooled,filtered, concentrated and purified by FCC (PE:EA=8:1) to give compound1a as a yellow solid.

Step 2:N-(2-((3-Bromophenyl)ethynyl)-4-fluorphenyl)-4-methylbenzenesulfonamide(1b)

To a solution of compound 1a (3.50 g, 12.1 mmol) in DCM (50 mL) wasadded pyridine (3.5 mL), 4-methylbenzene-1-sulfonyl chloride (4.58 g,24.1 mmol) and DMAP (350 mg). The mixture was stirred at rt overnight,diluted with CH₂C2 (300 mL) and subsequently washed with 2N HCl (3×30mL) and brine (30 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated and purified by FCC (PE:EA=5:1) to give compound1b as a white solid.

Step 3:3-(2-(3-Bromophenyl)-5-fluoro-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile(1)

To a solution of compound 1b (4.20 g, 9.48 mmol) in CH₃CN (60 mL) wasadded 3-bromothiophene-2-carbonitrile (3.67 g, 14.2 mmol), K₂CO₃ (2.62g, 10.0 mmol) and Pd(PPh₃)₄ (1.09 g, 0.95 mmol) under N₂. The mixturewas stirred at 100° C. for 2 h, cooled, poured into EA (400 mL) andwashed with water (50 mL) and brine (50 mL). The organic layer was driedover Na₂SO₄, filtered, concentrated and purified by FCC (EA:PE=1:3) togive compound 1 as a white solid.

Example 1/1 to 1/149

The following Examples were prepared similar as described for Example 1using the appropriate building blocks.

# building block(s) structure analytical data 1/1

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Separation of both isomers under the following conditions: Instrument:SFC-80 (Thar, Waters) Column: OJ 20 × 250 mm, 10 μm (Daicel) Columntemperature: 35° C. Mobile phase: CO₂/MeOH (0.2% NH₄ ⁺OMe⁻) = 70/30 Flowrate: 80 g/min Back pressure: 100 bar Detection wavelength: 214 nm Cycletime: 2 min Sample solution: 180 mg dissolved in 30 mL MeOH Injectionvolume: 1 mL 1/6

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¹H-NMR (500 MHz, DMSO-d₆) δ: 8.25 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 5.5Hz, 1H), 7.57 (dd, J = 3.0, 5.0 Hz, 1H), 7.49 (dd, J = 4.5, 8.5 Hz, 1H),7.45-7.43 (m, 3H), 7.36 (d, J = 4.0 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H),7.11 (dd, J = 1.3, 4.8 Hz, 1H), 6.98 (d, J = 5.0 Hz, 1H), 2.31 (s, 3H);MS: 482.7 (M + Na)⁺. 1/24

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¹H-NMR (500 MHz, DMSO-d₆) δ: 8.21 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 5.0Hz, 1H), 7.55-7.51 (m, 2H), 7.46 (d, J = 7.5 Hz 1H), 7.40 (t, J = 7.5Hz, 1H), 6.99 (d, J = 5.0 Hz, 1H), 6.94- 6.89 (m, 4H), 2.23 (s, 3H),2.06 (s, 6H); MS: 510.8 (M + Na)⁺. 1/27

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.33 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.98 (d, J= 5.0 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.63- 7.43 (m, 7H), 7.05- 6.95(m, 3H); MS: 519.3 (M + Na)⁺. 1/28

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.20 (d, J = 10.5 Hz, 1H), 8.02 (d, J = 6.5Hz, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.67-7.66 (m, 1H), 7.50- 7.30 (m,4H), 7.09 (dd, J = 4.5, 6.5 Hz, 1H), 7.04 (d, J = 6.0 Hz, 1H), 3.63 (s,3H); MS: 450.8 (M + 1)⁺. 1/29

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¹H-NMR (500 MHz, DMSO-d₆) δ: 8.16 (d, J = 9.5 Hz, 1H), 8.04 (d, J = 5.0Hz, 1H), 7.74 (d, J = 4.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.49 (d, J= 8.5 Hz, 2H), 7.22-7.21 (m, 1H). 7.16-7.12 (m, 2H), 7.03 (d, J = 5.5Hz, 1H), 6.78 (s, 1H), 3.76 (s, 3H); MS: 510.8 (M + 1)⁺. 1/40

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.03 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 1.5Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.19- 7.17 (m, 1H), 7.11- 7.09(m, 1H), 7.05 (dd, J = 2.5, 8.5 Hz, 1H), 7.01 (d, J = 5.5 Hz, 1H), 3.91(s, 3H); MS: 510.8 (M + 1)⁺. 1/41

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.82 (d, 4.0 Hz, 1H), 8.62 (s, 1H), 8.30(d, J = 8.0 Hz, 1H), 8.01 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H),7.58- 7.53 (m, 2H), 7.46- 7.35 (m, 5H), 7.30 (d, J = 7.0 Hz, 2H), 6.97(d, J = 4.5 Hz, 1H); MS: 441.9 (M + 1)⁺. 1/42

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.19 (d, J = 8.5 Hz, 1H), 8.05- 8.02 (m,2H), 7.57- 7.54 (m, 1H), 7.46- 7.33 (m, 7H), 6.97 (d, J = 5.0 Hz, 1H),2.63 (s, 3H); MS: 462.1 (M + 1)⁺. 1/43

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¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (dd, J = 9.2, 4.4 Hz, 1H), 8.09 (d, J =1.6 Hz, 1H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.60-7.15 (m, 13H), 6.73(dd, J = 2.4, 8.4 Hz, 1H), 6.71 (t, J = 55.6 Hz, 1H), 3.96 (s, 3H), 1.88(s, 3H). C1/ 123

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¹H-NMR (500 MHz, DMSO-d₆) δ: 8.32 (dd, J = 9.3, 4.3 Hz, 1H), 8.24 (d, J= 8.5 Hz, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.72-7.59 (m, 5H), 7.45 (dt, J= 2.5, 9.0 Hz, 1H), 7.35-7.24 (m, 2H), 7.23 (d, J = 2.5 Hz, 1H), 7.25(d, J = 8.5 Hz, 1H), 7.08 (t, J = 55.0 Hz, 1H). 1/ 140

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Example 2

Step 1:3-(5-Fluoro-2-(3-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile(2a)

To a solution of compound 1 (2.61 g, 4.73 mmol) in dioxane (40 mL) wasadded B₂Pin₂ (1.44 g, 5.68 mmol), KOAc (928 mg, 9.46 mmol) andPd(dppf)Cl₂ (344 mg, 0.47 mmol). The mixture was stirred at 80° C.overnight under N₂, cooled, filtered, concentrated and purified by FCC(EA:PE=1:3) to give compound 2a as a white solid.

Step 2:3-(2-(2′-Chloro-4′-((dimethylamino)methyl)-[1,1′-biphenyl]-3-yl)-5-fluoro-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile(2)

To a solution of compound 2a (150 mg, 0.25 mmol) in dioxane (8 mL) wasadded 1-(4-bromo-3-chlorophenyl)-N,N-dimethylmethanamine (65 mg, 0.26mmol), Cs₂CO₃ (163 mg, 0.50 mmol) and Pd(PPh₃)₄ (30 mg, 25 μmol). Themixture was stirred at 100° C. overnight under N₂, cooled, filtered,concentrated and purified by prep-HPLC to give compound 2 as a whitesolid. ¹H-NMR (500 MHz, DMSO-d) δ: 8.29 (dd, J=9.5, 4.5 Hz, 1H), 8.02(d, J=5.0 Hz, 1H), 7.51-7.32 (m, 8H), 7.26-7.17 (m, 4H), 7.02-6.99 (m,2H), 3.42 (s, 2H), 2.21 (s, 3H), 2.18 (s, 6H); MS: 639.9 (M+1)⁺.

Example 2/1 to 2/34

The following Examples were prepared similar as described for Example 2(and optionally for Example 1) using the appropriate building blocks.

# building block(s) structure analytical data 2/1

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.83 (d, J =5.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.50-7.43 (m, 4H), 7.35-7.26 (m,4H), 7.20-7.15 (m, 3H), 7.05 (dd, J = 8.5, 2.5 Hz, 1H), 6.96 (d, J = 5.0Hz, 1H), 4.19 (s, 2H), 2.29 (s, 3H); MS: 611.8 (M + 1)⁺. 2/2

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.81 (d, J =5.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.52-7.41 (m, 4H), 7.29-7.25 (m,4H), 7.16-7.14 (m, 2H), 7.06 (dd, J = 8.5, 3.0 Hz, 1H), 6.97 (s, 1H),6.93 (d, J = 5.0 Hz, 1H), 2.25 (s, 3H), 1.54 (s, 6H); MS: 639.0 (M +1)⁺. 2/3

2/4

2/5

2/6

2/7

2/8

2/9

2/10

2/11

2/12

2/13

2/14

P2/15

2/16

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.34-8.29 (m, 1H), 8.01 (d, J = 5.0 Hz,1H), 7.96 (d, J = 1.5 Hz, 1H), 7.86-7.84 (m, 2H), 7.61 (s, 1H), 7.53 (t,J = 7.5 Hz, 1H), 7.41-7.28 (m, 6H), 7.21-7.18 (m, 1H), 7.08 (d, J = 5.5Hz, 1H), 5.59-5.55 (m, 1H), 4.96-4.94 (m, 2H), 3.45 (s, 3H), 2.27 (s,3H); MS: 691.8 (M + 18)⁺. P2/17

2/18

¹H-NMR (500 MHz, CD₃OD) δ: 8.44-8.41 (m, 1H), 8.16 (s, 1H), 7.85-7.76(m, 4H), 7.51-7.48 (m, 1H), 7.39-7.26 (m, 5H), 7.19-7.17 (m, 2H),7.06-7.01 (m, 2H), 3.23 (s, 3H), 2.26 (s, 3H), 1.77 (s, 6H); MS: 730.1(M + 18)⁺. 2/19

2/20

2/21

2/22

2/23

2/24

2/25

2/26

2/27

2/28

2/29

2/30

2/31

2/32

2/33

2/34

Example 3

2-(2-Chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-[1,1′-biphenyl]-4-yl)-2-(dimethylamino)aceticAcid (3)

To a solution of compound 2/3 (80 mg, 0.11 mmol) in THF (8 mL), MeOH (3mL) and H₂O (3 mL) was added LiOH.H₂O (24 mg, 0.57 mmol). The mixturewas stirred at rt for 30 min, concentrated, diluted with H₂O (6 mL),adjusted to pH=3 with 2N HCl and extracted with EA (2×50 mL). Thecombined organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by prep-HPLC to afford compound 3 as a white solid. ¹H-NMR (500MHz, DMSO-d₆) δ: 8.41 (dd, J=9.3, 4.3 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H),7.74 (d, J=2.0 Hz, 1H), 7.57 (dd, J=7.8, 1.7 Hz, 1H), 7.50-7.41 (m, 4H),7.30-7.25 (m, 3H), 7.18-7.15 (m, 2H), 7.07-7.05 (m, 2H), 6.95 (d, J=5.0Hz, 1H), 4.53 (s, 1H), 2.84 (s, 6H), 2.27 (s, 3H); MS: 683.8 (M+1)+.

Example 3/1 to 3/73

The following Examples were saponified similar as described for Example3 using the appropriate starting material (ester).

# starting material structure analytical data 3/1

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 4.5, 9.0 Hz, 1H), 7.80 (d, J =5.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32-7.17 (m, 7H), 7.04 (dd, J =2.8, 8.8 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J = 5.5 Hz, 1H), 2.36 (s, 3H),1.83-1.80 (m, 1H), 1.43 (s, 3H), 1.31-1.29 (m, 1H), 1.22-1.19 (m, 1H);MS: 568.8 (M − 1)⁻. 3/2

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (dd, J = 4.3, 8.8 Hz, 1H), 7.74 (d, J =5.0 Hz, 1H), 7.36-7.21 (m, 8H), 7.13- 7.04 (m, 2H), 6.75 (d, J = 5.0 Hz,1H), 2.35 (s, 3H), 1.94-1.92 (m, 1H), 1.63-1.62 (m, 1H), 1.38 (s, 3H),1.20- 1.17 (m, 1H); MS: 568.8 (M − 1)⁻. 3/3

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.21 (dd, J = 4.5, 9.0 Hz, 1H), 6.68 (d, J= 9.0 Hz, 2H), 7.31-7.26 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 6.97 (dd, J= 2.5, 9.0 Hz, 1H), 6.75 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H),6.48 (dd, J = 2.0, 8.0 Hz, 1H), 6.39 (d, J = 6.0 Hz, 1H), 6.26 (s, 1H),3.93 (t, J = 8.0 Hz, 2H), 3.79 (t, J = 6.5 Hz, 2H), 3.60 (s, 3H),3.54-3.47 (m, 1H), 2.32 (s, 3H); MS: 577.1 (M + 1)⁺. 3/4

¹H-NMR (500 MHz, CD₃OD) δ: 8.36 (dd, J = 4.3, 8.8 Hz, 1H), 7.60 (d, J =5.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.25-7.17 (m, 4H), 6.84 (dd, J =2.5, 8.5 Hz, 1H), 6.75-6.70 (m, 2H), 6.55 (dd, J = 1.8, 8.3 Hz, 1H),6.19 (t, J = 55.0 Hz, 1H), 6.16 (s, 1H), 3.99-3.82 (m, 4H), 3.58-3.52(m, 1H), 2.38 (s, 3H); MS: 597.1 (M + 1)⁻. 3/5

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.64 (br s, 1H), 9.31 (d, J = 1.0 Hz, 1H),8.26 (dd, J = 4.0, 9.0 Hz, 1H), 8.10 (dd, J = 1.3, 4.8 Hz, 1H), 7.40-7.32 (m, 5H), 7.14-7.06 (m, 3H), 6.60 (br s, 1H), 6.46 (dd, J = 1.8, 8.3Hz, 1H), 6.20 (br s, 1H), 3.87 (t, J = 8.0 Hz, 2H), 3.74 (t, J = 6.5 Hz,2H), 3.54-3.48 (m, 1H), 2.33 (s, 3H); MS: 575.0 (M + 1)⁺. 3/6

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.23 (dd, J = 4.5, 9.0 Hz, 1H), 7.46 (d, J= 5.0 Hz, 1H), 7.33-7.27 (m, 5H), 7.14 (t, J = 7.8 Hz, 1H), 6.87 (dd, J= 2.5, 8.5 Hz, 1H), 6.63-6.60 (m, 2H), 6.45 (dd, J = 2.0, 8.0 Hz, 1H),6.18 (s, 1H), 4.14-4.09 (m, 1H), 3.89-3.73 (m, 5H), 3.54-3.48 (m, 1H),2.99 (s, 3H), 2.31 (s, 3H); MS: 591.1 (M + 1)⁺. 3/7

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.69 (br s, 1H), 11.24 (s, 1H), 8.25 (dd,J = 4.3, 9.3 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 7.38-7.29 (m, 6H), 7.13(d, J = 7.8 Hz, 1H), 6.83 (dd, J = 2.5, 8.5 Hz, 1H), 6.72 (d, J = 5.5Hz, 1H), 6.60-6.57 (m, 1H), 6.45 (dd, J = 2.0, 8.0 Hz, 1H), 6.19 (s,1H), 3.91-3.87 (m, 2H), 3.79-3.75 (m, 2H), 3.54-3.50 (m, 1H), 2.32 (m,3H); MS: 590.0 (M + 1)⁺. 3/8

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 4.8, 9.3 Hz, 1H), 8.24 (d, J= 5.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.42-7.33 (m, 3H), 7.23 (s,1H), 7.15-7.11 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.52 (d, J = 7.5 Hz,1H), 6.47 (dd, J = 1.3, 8.3 Hz, 1H), 6.17 (s, 1H), 3.86 (t, J = 8.0 Hz,2H), 3.75 (t, J = 6.5 Hz, 2H), 3.45-3.40 (m, 1H), 2.28 (s, 3H); MS:569.8 (M − 1)⁻. 3/9

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 4.5, 9.5 Hz, 1H), 7.98 (d, J= 4.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.54-7.50 (m, 4H), 7.37-7.33 (m, 1H),7.14-7.11 (m, 2H), 6.93 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H),6.45 (dd, J = 1.8, 8.3 Hz, 1H), 6.18 (s, 1H), 3.83 (t, J = 7.8 Hz, 2H),3.74 (t, J = 6.3 Hz, 2H), 3.34-3.30 (m, 1H); MS: 557.9 (M + 1)⁺. 3/10

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 4.0, 9.0 Hz, 1H), 7.98 (d, J= 5.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.37-7.33 (m, 3H), 7.16-7.11(m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.48 (dd, J= 1.5, 8.0 Hz, 1H), 6.21 (s, 1H), 3.89 (t, J = 7.5 Hz, 2H), 3.77 (t, J =6.3 Hz, 2H), 3.49-3.44 (m, 1H), 2.63 (q, J = 7.5 Hz, 2H), 1.12 (t, J =7.5 Hz, 3H); MS: 586.8 (M + 1)⁺. 3/11

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 4.3, 9.3 Hz, 1H), 7.99 (d, J= 5.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.52-7.23 (m, 4H), 7.15-7.12(m, 2H), 6.95 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.49-6.48(m, 1H), 6.27 (s, 1H), 3.90 (t, J = 8.0 Hz, 2H), 3.79 (t, J = 6.5 Hz,2H), 3.46-3.41 (m, 1H); MS: 623.7 (M + 1)⁺. 3/12

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 4.5, 9.0 Hz, 1H), 7.97 (d, J= 5.0 Hz, 1H), 7.37-7.30 (m, 3H), 7.27 (s, 1H), 7.15-7.10 (m, 2H), 6.94(d, J = 5.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.46 (dd, J = 1.8, 8.3Hz, 1H), 6.14 (s, 1H), 3.84 (t, J = 8.0 Hz, 2H), 3.74 (t, J = 6.5 Hz,2H), 3.41- 3.35 (m, 1H), 2.88-2.80 (m, 4H), 2.02-1.97 (m, 2H); MS: 598.2(M + 1)⁺. 3/13

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.38 (dd, J = 4.0, 9.5 Hz, 1H), 8.18 (s,1H), 8.06-7.96 (m, 4H), 7.76-7.68 (m, 2H), 7.46 (d, J = 9.0 Hz, 1H),7.39-7.36 (m, 1H), 7.15-7.12 (m, 2H), 6.95 (d, J = 5.0 Hz, 1H), 6.59 (d,J = 7.0 Hz, 1H), 6.45 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 3.69-3.59 (m,4H), 3.42- 3.32 (m, 1H); MS: 608.2 (M + 1)⁺. 3/14

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.16 (dd, J = 4.5, 9.0 Hz, 1H), 7.98 (d, J= 5.5 Hz, 1H), 7.36-7.17 (m, 4H), 7.05 (t, J = 7.5 Hz, 2H), 6.99 (d, J =5.0 Hz, 1H), 6.45-6.40 (m, 2H), 5.97 (s, 1H), 3.79 (t, J = 8.0 Hz, 2H),3.68 (t, J = 6.3 Hz, 2H), 3.45-3.40 (m, 1H), 2.36 (s, 3H); MS: 589.9(M + 1)⁺. 3/15

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.42 (d, J = 8.5 Hz, 1H), 8.03-8.01 (m,1H), 7.83 (d, J = 5.0 Hz, 1H), 7.79 (s, 1H), 7.67-7.62 (m, 2H), 7.56-7.53 (m, 1H), 7.42-7.39 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 (d, J =8.5 Hz, 2H), 6.97 (d, J = 5.0 Hz, 1H), 4.26 (s, 2H), 2.35 (s, 3H); MS:576.7 (M + 1)⁺. 3/16

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.07 (br s, 1H), 8.28 (d, J = 8.0 Hz, 1H),8.02 (d, J = 5.0 Hz, 1H), 7.53- 7.50 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H),7.38 (d, J = 4.0 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 3.5 Hz,1H), 6.99 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 2.97 (s, 2H),2.31 (s, 3H), 1.09 (s, 6H); MS: 559.0 (M − 1)⁻. 3/17

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J = 11.0 Hz, 1H), 8.05 (d, J = 6.0Hz, 1H), 7.54-7.32 (m, 8H), 7.04 (d, J = 6.0 Hz, 1H), 6.91 (d, J = 2.0Hz, 1H), 2.39-2.34 (m, 1H), 2.32 (s, 3H), 1.75-1.70 (m, 1H), 1.39-1.35(m, 1H), 1.20-1.15 (m, 1H); MS: 562.1 (M + 18)⁺. 3/18

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (d, J = 10.0 Hz, 1H), 7.80 (d, J = 6.5Hz, 1H), 7.65-7.49 (m, 3H), 7.43-7.21 (m, 9H), 6.96 (d, J = 6.5 Hz, 1H),6.35 (d, J = 20.0 Hz, 1H), 2.36 (s, 3H); MS: 524.6 (M + 1)⁺. 3/19

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.47 (br s, 1H), 8.25 (d, J = 10.5 Hz,1H), 8.07 (d, J = 6.5 Hz, 1H), 7.70 (d, J = 20.0 Hz, 1H), 7.56-7.51 (m,4H), 7.42-7.32 (m, 4H), 7.23 (d, J = 4.5 Hz, 1H), 7.09 (d, J = 6.5 Hz,1H), 6.18 (d, J = 20.0 Hz, 1H), 2.31 (s, 3H); MS: 530.7 (M + 1)⁺. 3/20

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.39 (br s, 1H), 8.29 (d, J = 8.5 Hz, 1H),7.98 (d, J = 5.0 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.40-7.28 (m, 9H),7.06 (s, 1H), 6.92 (d, J = 4.0 Hz, 1H), 2.30 (s, 3H), 1.36 (s, 6H); MS:563.1 (M + Na)⁺. 3/21

¹H-NMR (500 MHz, CD₃OD) δ: 8.26 (dd, J = 4.5, 9.0 Hz, 1H), 8.10 (d, J =1.0 Hz, 1H), 7.99 (dd, J = 1.8, 7.8 Hz, 1H), 7.86 (d, J = 5.5 Hz, 1H),7.56- 7.51 (m, 3H), 7.44 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25-7.21(m, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.98 (d, J = 4.5 Hz, 1H), 3.48(d, J = 12.5 Hz, 2H), 2.53-2.48 (m, 2H), 1.47 (d, J = 12.5 Hz, 2H),1.33-1.28 (m, 1H), 0.86-0.77 (m, 5H); MS: 633.9 (M + 1)⁺. 3/22

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 4.5, 9.0 Hz, 1H), 8.09 (d, J =2.0 Hz, 1H), 8.00 (dd, J = 1.5, 7.5 Hz, 1H), 7.82 (d, J = 5.0 Hz, 1H),7.52- 7.44 (m, 3H), 7.39 (d, J = 8.0 Hz, 1H), 7.29-6.95 (m, 4H); MS:632.0 (M − 1)⁻. 3/23

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.41 (br s, 1H), 8.31 (dd, J = 4.5, 9.0Hz, 1H), 8.04-7.95 (m, 3H), 7.56- 7.48 (m, 3H), 7.42-7.34 (m, 4H),7.26-7.18 (m, 3H), 7.03 (d, J = 5.0 Hz, 1H), 2.08 (s, 3H); MS: 642.9 (M− 1)⁻. 3/24

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29-8.26 (m, 1H), 8.01 (d, J = 5.5 Hz,1H), 7.65-7.55 (m, 2H), 7.45-7.35 (m, 3H), 7.26 (d, J = 5.0 Hz, 1H),7.18-7.14 (m, 1H), 7.06-7.03 (m, 1H), 6.97 (d, J = 5.0 Hz, 1H), 6.91 (s,1H), 2.35-2.30 (m, 1H), 1.70 (s, 1H), 1.41- 1.37 (m, 1H), 1.17 (s, 1H);MS: 575.0 (M − 1)⁻. 3/25

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.66 (br s, 1H), 8.31-8.26 (m, 1H), 7.76(d, J = 5.5 Hz, 1H), 7.46-7.33 (m, 6H), 7.20-7.15 (m, 2H), 6.60 (d, J =7.5 Hz, 1H), 6.53-6.49 (m, 1H), 6.23 (s, 1H), 3.92 (t, J = 8.0 Hz, 2H),3.79 (t, J = 6.5 Hz, 2H), 3.54-3.50 (m, 1H), 2.34 (s, 3H); MS: 572.1(M + 1)⁺. 3/26

¹H-NMR (500 MHz, CD₃OD) δ: 8.42- 8.39 (m, 1H), 7.72 (d, J = 1.5 Hz, 1H),7.36 (d, J = 8.5 Hz, 2H), 7.28- 7.14 (m, 5H), 6.65 (d, J = 8.0 Hz, 1H),6.66-6.64 (m, 1H), 6.60-6.57 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H), 6.20 (s,1H), 4.01 (t, J = 7.5 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.54-3.50 (m,1H), 2.38 (s, 3H); MS: 556.2 (M + 1)⁺. 3/27

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.23-8.19 (m, 1H), 7.32-7.26 (m, 6H), 7.14(t, J = 7.5 Hz, 1H), 6.84-6.81 (m, 1H), 6.66-6.62 (m, 1H), 6.55 (d, J =5.0 Hz, 1H), 6.45-6.42 (m, 1H), 6.16 (s, 3H), 3.90-3.85 (m, 2H),3.77-3.73 (m, 2H), 3.52-3.49 (m, 1H), 3.25-3.19 (m, 2H), 2.48-2.33 (m,2H), 2.31 (s, 1H); MS: 591.0 (M + 1)⁺. 3/28

¹H-NMR (500 MHz, CD₃OD) δ: 8.40- 8.37 (m, 1H), 7.54 (d, J = 5.5 Hz, 1H),7.34 (d, J = 8.0 Hz, 2H), 7.25- 7.19 (m, 4H), 7.05-7.03 (m, 1H), 6.75(d, J = 5.0 Hz, 1H), 6.67-6.59 (m, 2H), 6.26 (s, 1H), 4.05-4.01 (m, 2H),3.95-3.92 (m, 2H), 3.60-3.57 (m, 1H), 2.65 (s, 3H), 2.38 (s, 3H), 2.33(s, 3H); MS: 618.0 (M + 1)⁺. C3/29

¹H-NMR (500 MHz, CD₃OD) δ: 8.41- 8.38 (m, 1H), 7.63 (d, J = 1.5 Hz, 1H),7.40-7.35 (m, 3H), 7.30-7.21 (m, 5H), 6.68-6.61 (m, 2H), 6.18 (d, J =1.5 Hz, 1H), 4.03-3.99 (m, 2H), 3.93- 3.89 (m, 2H), 3.56-3.53 (m, 1H),2.37 (s, 3H); MS: 572.1 (M + 1)⁺. 3/30

¹H-NMR (500 MHz, CD₃OD) δ: 8.35- 8.32 (m, 1H), 7.62 (d, J = 5.0 Hz, 1H),7.31-7.15 (m, 7H), 6.78-6.75 (m, 1H), 6.66 (br s, 2H), 6.51-6.48 (m,1H), 3.98-3.79 (m, 4H), 3.55-3.50 (m, 1H), 2.37 (s, 3H); MS: 615.1 (M +1)⁺. 3/31

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.27-8.23 (m, 1H), 7.62 (d, J = 7.0 Hz,1H), 7.41 (t, J = 8.0 Hz, 1H), 7.35-7.28 (m, 5H), 7.20 (t, J = 7.0 Hz,1H), 7.09 (t, J = 7.0 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.63-6.56 (m,2H), 6.38 (d, J = 6.5 Hz, 1H), 6.05-6.01 (m, 1H), 4.41-4.13 (m, 4H),3.82-3.79 (m, 2H), 3.70-3.66 (m, 2H), 3.59-3.55 (m, 1H), 3.43-3.39 (m,1H), 2.33 (s, 3H); MS: 597.2 (M + 1)⁺. 3/32

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29-8.26 (m, 1H), 7.98 (d, J = 5.1 Hz,1H), 7.41 (d, J = 8.4 Hz, 2H), 7.37-7.31 (m, 3H), 7.17-7.09 (m, 2H),6.94 (d, J = 5.1 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.48 (dd, J = 8.1,1.8 Hz, 1H), 6.20 (s, 1H), 3.88 (t, J = 7.8 Hz, 2H), 3.77 (t, J = 6.5Hz, 2H), 3.47- 3.43 (m, 1H), 2.33 (s, 3H); MS: 569.7 (M − 1)⁻. 3/33

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30-8.26 (m, 1H), 7.98 (d, J = 5.1 Hz,1H), 7.46 (d, J = 8.9 Hz, 2H), 7.35 (td, J = 9.2, 2.5 Hz, 1H), 7.16-7.10 (m, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.56(d, J = 7.5 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 6.23 (s, 1H), 3.90 (t, J= 7.9 Hz, 2H), 3.77-3.80 (m, 5H), 3.48-3.44 (m, 1H); MS: 578.8 (M + 1)⁺.3/34

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.31-8.28 (m, 1H), 7.99 (d, J = 5.1 Hz,1H), 7.92 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.39 (td, J =9.1, 2.5 Hz, 1H), 7.15-7.11 (m, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.54-6.47(m, 2H), 6.24 (s, 1H), 3.89 (t, J = 7.9 Hz, 2H), 3.78 (t, J = 6.4 Hz,2H), 3.44-3.47 (m, 1H); MS: 625.8 (M + 1)⁺. 3/35

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30-8.27 (m, 1H), 7.99 (d, J = 5.1 Hz,1H), 7.73 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.40-7.35 (m,1H), 7.15-7.12 (m, 2H), 7.09 (t, J = 55.5 Hz, 1H), 6.96 (d, J = 5.1 Hz,1H), 6.55 (d, J = 7.5 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H),3.88 (t, J = 7.9 Hz, 2H), 3.77 (t, J = 6.5 Hz, 2H), 3.42-3.48 (m, 1H);MS: 607.8 (M + 1)⁺. 3/36

¹H-NMR (500 MHz, CD₃OD) δ: 8.24- 8.21 (m, 1H), 7.79 (d, J = 5.1 Hz, 1H),7.23-7.15 (m, 2H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.86 (d, J = 5.1 Hz,1H), 6.77 (d, J = 7.6 Hz, 1H), 6.56- 6.53 (m, 2H), 4.05-4.01 (m, 2H),3.94-3.90 (m, 2H), 3.50-3.56 (m, 1H), 3.47 (d, J = 12.9 Hz, 2H), 2.48(t, J = 11.7 Hz, 2H), 1.49 (dd, J = 13.0, 2.1 Hz, 2H), 1.39-1.26 (m,1H), 0.90-0.76 (m, 5H); MS: 579.0 (M + 1)⁺. 3/37

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.77 (s, 1H), 8.27 (dd, J = 9.2, 4.4 Hz,1H), 7.99 (d, J = 5.1 Hz, 1H), 7.45-7.28 (m, 5H), 7.19-7.08 (m, 2H),6.95 (d, J = 5.1 Hz, 1H), 6.59-6.57 (m, 1H), 6.51-6.47 (m, 1H), 6.21 (s,1H), 3.92 (d, J = 7.2 Hz, 2H), 3.54 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H),1.52 (s, 3H); MS: 586.2 (M + 1)⁺. 3/38

¹H-NMR (400 MHz, CD₃OD) δ: 8.40 (dd, J = 9.2, 4.4 Hz, 1H), 7.88 (d, J =5.1 Hz, 1H), 7.41-7.57 (m, 3H), 7.35- 7.20 (m, 5H), 7.10-6.98 (m, 3H),3.73-3.69 (m, 2H), 3.47-3.41 (m, 2H), 2.80-2.67 (m, 1H), 2.36 (s, 3H),2.26 (d, J = 14.1 Hz, 2H), 2.13-1.98 (m, 2H); MS: 600.2 (M + 1)⁺. 3/39

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.14 (s, 1H), 8.30 (dd, J = 9.2, 4.4 Hz,1H), 8.00-7.97 (m, 1H), 7.43-7.20 (m, 7H), 7.17-7.08 (m, 2H), 7.06-6.91(m, 2H), 3.62-3.29 (m, 1H), 3.10-2.92 (m, 1H), 2.50-2.39 (m, 2H), 2.32(s, 3H), 2.24-2.02 (m, 2H); MS: 568.7 (M − 1)⁻. 3/40

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.68 (s, 1H), 8.28 (dd, J = 9.2, 4.4 Hz,1H), 7.98 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.44-7.32 (m,3H), 7.28-7.17 (m, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.54 (dd, J = 8.7, 2.8Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 4.02-3.93 (m, 2H), 3.90-3.77 (m, 2H),3.59-3.48 (m, 1H), 2.36 (s, 3H); MS: 606.1 (M + 1)⁺. 3/41

¹H-NMR (500 MHz, CDCl₃) δ: 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 7.49 (d, J =5.1 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.20-7.12 (m, 3H), 7.05 (dd, J =8.4, 2.4 Hz, 1H), 6.90 (t, J = 8.9 Hz, 1H), 6.83 (d, J = 5.1 Hz, 1H),6.56-6.49 (m, 1H), 6.39-6.35 (m, 1H), 4.12-3.98 (m, 4H), 3.63-3.55 (m,1H), 2.35 (s, 3H); MS: 590.1 (M + 1)⁺. 3/42

¹H-NMR (500 MHz, CD₃OD) δ: 8.34- 8.29 (m, 1H), 7.78 (d, J = 5.0 Hz, 1H),7.34-7.15 (m, 6H), 6.87 (d, J = 5.0 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H),6.57 (dd, J = 1.5 Hz, 1.0 Hz, 1H), 6.18 (s, 1H), 4.00 (t, J = 8.0 Hz,2H), 3.89 (t, J = 7.5 Hz, 2H), 3.58-3.54 (m, 1H), 2.38 (s, 3H); MS:589.7 (M + 1)⁺. 3/43

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.69 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H),7.99 (d, J = 6.5 Hz, 1H), 7.45- 7.32 (m, 5H), 7.14 (t, J = 9.5 Hz, 1H),6.95 (d, J = 6.0 Hz, 1H), 6.55-6.48 (m, 2H), 6.15 (s, 1H), 3.89 (t, J =9.5 Hz, 2H), 3.74 (t, J = 8.5 Hz, 2H), 3.54-3.49 (m, 1H), 2.34 (s, 3H);MS: 606.1 (M + 1)⁺. 3/44

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 5.0Hz, 1H), 7.52 (dd, J = 2.5, 2.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.35-7.31 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 5.0 Hz, 1H), 6.55(d, J = 7.5 Hz, 1H), 6.50-6.46 (m, 1H), 6.19 (s, 1H), 3.89-3.86 (m, 2H),3.78-3.74 (m, 2H), 3.45-3.40 (m, 1H), 2.33 (s, 3H); MS: 587.8 (M + 1)⁺.3/45

¹H-NMR (500 MHz, DMSO-d⁶) δ: 8.46 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 5.0Hz, 1H), 7.95-7.88 (m, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.56 (d, J= 7.5 Hz, 1H), 6.50 (dd, J = 1.5, 2.0 Hz, 1H), 6.20 (s, 1H), 3.93-3.87(m, 2H), 3.80-3.75 (m, 2H), 3.54-3.50 (m, 1H), 2.35 (s, 3H); MS: 579.1(M + 1)⁺. 3/46

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.12 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 5.0Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (t, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.96(d, J = 5.0 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.46 (dd, J = 1.5, 2.0Hz, 1H), 6.22 (s, 1H), 3.90-3.86 (m, 2H), 3.78-3.74 (m, 2H), 3.45-3.41(m, 1H), 2.36 (s, 3H), 2.31 (s, 3H); MS: 567.8 (M + 1)⁺. 3/47

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.81 (s, 1H), 8.33-8.29 (m, 1H), 8.10- 8.03(m, 3H), 7.85 (d, J = 10.0 Hz, 1H), 7.58-7.52 (m, 2H), 7.42-7.32 (m,4H), 7.27 (d, J = 10.0 Hz, 2H), 7.21 (dd, J = 3.0, 3.5 Hz, 1H), 7.08 (d,J = 6.0 Hz, 1H), 2.25 (s, 3H); MS: 594.1 (M + 1)⁺. 3/48

¹H-NMR (500 MHz, CD₃OD) δ: 8.43- 8.40 (m, 1H), 8.08 (d, J = 2.0 Hz, 1H),7.99 (dd, J = 10.0, 2.0 Hz, 1H), 7.83 (d, J = 6.5 Hz, 1H), 7.52-7.44 (m,3H), 7.38 (d, J = 10.0 Hz, 1H), 7.30-7.25 (m, 3H), 7.15 (d, J = 10.0 Hz,2H), 7.08-6.96 (m, 3H), 2.24 (s, 3H); MS: 624.7 (M − 1)⁻. 3/49

¹H-NMR (500 MHz, CD₃OD) δ: 8.44- 8.40 (m, 1H), 7.88-7.83 (m, 2H), 7.72(dd, J = 8.5, 1.5 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.51-7.45 (m, 2H),7.34- 7.27 (m, 5H), 7.18 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 8.5, 2.5 Hz,1H), 7.00 (d, J = 5.0 Hz, 1H), 2.30 (s, 3H); MS: 624.7 (M − 1)⁻. 3/50

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.41 (br s, 1H), 8.29-8.25 (m, 1H), 7.98(d, J = 5.0 Hz, 1H), 7.39-7.29 (m, 5H), 7.20-7.12 (m, 2H), 7.02-6.95 (m,2H), 6.72-6.65 (m, 2H), 3.33-3.30 (m, 2H), 2.83-2.79 (m, 2H), 2.32 (s,3H), 2.01-1.99 (m, 2H), 1.48-1.43 (m, 2H), 1.16 (s, 3H); MS: 614.0 (M +1)⁺. 3/51

¹H-NMR (500 MHz, DMSO-d₆) δ 13.03 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H),8.00 (d, J = 5.5 Hz, 1H), 7.61- 7.58 (m, 2H), 7.53-7.50 (m, 3H),7.41-7.34 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.00-6.96 (m, 2H), 6.87 (d,J = 7.5 Hz, 1H), 6.82 (s, 1H), 4.63 (s, 2H); MS: 549.0 (M + 1)⁺. 3/52

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.24 (s, 1H), 8.28 (dd, J = 9.2, 4.4 Hz,1H), 8.19 (s, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H),7.37-7.29 (m, 3H), 7.17-7.10 (m, 2H), 6.93 (d, J = 5.1 Hz, 1H),6.57-6.55 (m, 1H), 6.48-6.45 (m, 1H), 6.20 (s, 1H), 3.87-3.83 (m, 2H),3.73-3.70 (m, 2H), 3.52-3.39 (m, 1H), 2.33 (s, 3H), 1.36 (s, 6H); MS:657.0 (M + 1)⁺. 3/53

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.00 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H),8.00 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.61-7.56 (m, 4H),7.50-7.45 (m, 2H), 7.33-7.28 (m, 3H), 7.08 (d, J = 5.0 Hz, 1H), 7.00(dd, J = 11.4, 2.1 Hz, 1H), 6.69 (dd, J = 8.0, 2.2 Hz, 1H), 3.80 (s,1H), 2.33 (s, 3H); MS: 623.0 (M + 1)⁺. 3/54

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.02 (s, 1H), 10.68 (s, 1H), 8.08 (d, J =5.1 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.60-7.38 (m, 6H), 7.30-7.21 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 6.67 (dd, J =10.9, 2.3 Hz, 1H), 6.51 (dd, J = 8.1, 2.4 Hz, 1H), 2.29 (s, 3H); MS:609.2 (M + 1)⁺. 3/55

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.74 (br s, 1H), 8.30 (dd, J = 9.0, 5.0Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.49-7.34 (m, 7H), 7.27- 7.16 (m, 4H), 7.05 (d, J = 5.0Hz, 1H), 5.83 (br s, 1H), 2.24 (s, 3H), 1.65 (s, 3H); MS: 634.8 (M −1)⁻. 3/56

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.39 (s, 1H), 8.27-8.24 (m, 1H), 7.97 (s,1H), 7.93 (d, J = 7.0 Hz, 1H), 7.64-7.25 (m, 12H), 7.11 (s, 1H), 7.01(br s, 1H), 6.75-6.73 (m, 1H), 4.42-4.37 (m, 2H), 4.17-4.13 (m, 2H),3.67-3.63 (m, 1H); MS: 670.0 (M − 1)⁻. 3/57

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30-8.27 (m, 1H), 8.04 (d, J = 5.0 Hz,1H), 7.96 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 4H),7.45-7.38 (m, 5H), 7.21-7.19 (m, 1H), 7.09 (s, 1H), 7.04 (d, J = 5.0 Hz,1H); MS: 644.9 (M − 1)⁻. 3/58

¹H-NMR (500 MHz, CD₃OD) δ: 8.40 (dd, J = 9.5, 4.0 Hz, 1H), 7.71 (d, J =5.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.27-7.16 (m, 4H), 7.04-7.02 (m,1H), 6.91-6.89 (m, 1H), 6.80 (d, J = 5.5 Hz, 1H), 6.61 (d, J = 8.0 Hz,1H), 6.46 (s, 1H), 4.16-4.13 (m, 2H), 2.94- 2.90 (m, 1H), 2.35 (s, 3H),2.11-2.07 (m, 2H), 1.89-1.81 (m, 4H), 1.57-1.54 (m, 2H); MS: 626.2 (M +1)⁺. 3/59

¹H-NMR (500 MHz, CD₃OD) δ: 8.41- 8.38 (m, 1H), 8.07 (s, 1H), 7.97 (d, J= 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.60-7.32 (m, 8H), 7.31-7.24(m, 3H), 7.15-6.97 (m, 2H), 6.77 (t, J = 55.5 Hz, 1H), 6.69-6.66 (m,1H), 4.53-4.43 (m, 2H), 4.35-4.29 (m, 2H), 3.72-3.64 (m, 1H); MS: 686.0(M − 1)⁻. 3/60

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.2, 4.4 Hz, 1H), 7.79 (d, J =5.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H),7.32-7.15 (m, 2H), 7.08-7.01 (m, 2H), 6.88 (d, J = 5.0 Hz, 1H), 6.81 (t,J = 55.0 Hz, 1H), 6.73-6.67 (m, 2H), 3.53-3.50 (m, 2H), 2.76-2.70 (m,2H), 2.49-2.32 (m, 1H), 1.98-1.96 (m, 2H), 1.81-1.73 (m, 2H); MS: 634.0(M − 1)⁻. 3/61

¹H-NMR (400 MHz, CD₃COCD₃) δ: 8.38-8.34 (m, 1H), 8.07 (s, 1H), 8.00 (d,J = 7.9 Hz, 1H), 7.71 (s, 4H), 7.63-7.23 (m, 9H), 7.14-6.72 (m, 3H),3.61-3.54 (m, 2H), 3.52-2.98 (m, 3H); MS: 705.0 (M + 1)⁺. 3/62

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (dd, J = 9.2, 4.3 Hz, 1H), 8.09 (s, 1H),8.00 (br s, 1H), 7.76-7.14 (m, 14H), 6.93-6.63 (m, 2H), 4.61-3.78 (m,4H), 2.81 (s, 3H); MS: 719.0 (M + 1)⁺. 3/63

¹H-NMR (400 MHz, CD₃OD) δ: 8.40- 8.36 (m, 1H), 8.10 (s, 1H), 8.00 (d, J= 5.5 Hz, 1H), 7.58-7.23 (m, 11H), 6.85-6.80 (m, 2H), 6.75 (t, J = 55.5Hz, 1H), 4.76-4.73 (m, 1H), 4.58-4.54 (m, 1H), 4.25-4.12 (m, 1H),4.10-4.09 (m, 1H), 3.89-3.86 (m, 1H); MS: 691.9 (M − 1)⁻. 3/64

¹H-NMR (500 MHz, DMSO-d₆) δ: 11.11 (br s, 1H), 8.30 (dd, J = 4.5, 9.5Hz, 1H). 7.99 (d, J = 5.5 Hz, 1H), 7.39-6.94 (m, 11H), 2.13 (s, 3H),1.79-1.76 (m, 6H), 1.65-1.62 (m, 6H); MS: 622.8 (M − 1)⁻. 3/65

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J = 4.3, 9.3 Hz, 1H), 7.99 (d, J= 5.0 Hz, 1H), 7.39-6.91 (m, 11H), 3.33-3.26 (m, 1H), 2.95-2.90 (m, 1H),2.41-1.81 (m, 11H); MS: 608.8 (M − 1)⁻. 3/66

¹H-NMR (400 MHz, CDCl₃) δ: 8.28- 8.14 (m, 3H), 7.72-7.37 (m, 11H),6.79-6.77 (m, 1H), 2.96-2.93 (m, 4H), 1.16-1.10 (m, 4H), 0.75 (s, 6H);MS: 593.7 (M − 1)⁻. 3/67

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (dd, J = 9.3, 4.8 Hz, 1H), 8.04 (d, J =7.5 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 2H), 7.54(d, J = 8.0 Hz, 2H), 7.32 (dt, J = 2.5, 9.3 Hz, 1H), 7.12 (t, J = 8.0Hz, 1H), 6.90 (dd, J = 2.5, 8.5 Hz, 1H), 6.80 (t, J = 55.8 Hz, 1H), 6.32(d, J = 7.5 Hz, 1H), 6.53 (dd, J = 1.5, 8.0 Hz, 1H), 6.21 (t, J = 1.8Hz, 1H), 3.96 (br s, 2H), 3.85 (br s, 2H), 3.57-3.51 (m, 1H); MS: 727.2(M + 1)⁺. 3/68

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.4, 4.4 Hz, 1H), 8.06-8.03 (m,2H), 7.71 (t, J = 8.3 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.49 (d, J =8.0 Hz, 2H), 7.35-7.21 (m, 3H), 7.05-6.84 (m, 4H), 2.42-2.34 (m, 1H),1.70-1.19 (m, 3H); MS: 610.0 (M − 1)⁻. 3/69

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (dd, J = 9.3, 4.3 Hz, 1H), 8.07 (d, J =1.5 Hz, 1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.55-7.47 (m, 8H), 7.39 (t,J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 2.5, 9.2 Hz,1H), 7.26 (br s, 1H), 7.10-6.59 (m, 4H); MS: 670.9 (M − 1)⁻. 3/70

¹H-NMR (500 MHz, CD₃OD) δ: 8.57 (s, 1H), 8.09-8.07 (m, 3H), 8.00 (dd, J= 8.3, 1.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.61-7.43 (m, 7H), 7.36(d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.70 (t, J = 55.5 Hz, 1H), 6.14 (d, J= 1.0 Hz, 1H); MS: 681.1 (M + 1)⁺. 3/71

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 4.3, 9.3 Hz, 1H), 8.07-7.97 (m,2H), 7.70 (t, J = 8.0 Hz, 1H), 7.53-7.44 (m, 7H), 7.34 (dt, J = 2.5, 9.0Hz, 1H), 6.94-6.91 (m, 2H), 6.70- 6.65 (m, 2H), 6.68 (t, J = 55.5 Hz,1H), 4.71 (s, 2H); MS: 712.0 (M − 1)⁻. 3/72

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 9.0, 4.5 Hz, 1H), 8.17-7.92 (m,2H), 7.71 (t, J = 8.0 Hz, 1H), 7.57-7.48 (m, 7H), 7.36-7.29 (m, 3H),6.95-6.92 (m, 2H), 6.65 (t, J = 55.8 Hz, 1H), 1.75 (s, 3H); MS: 726.0 (M− H)⁻. 3/73

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 4.3, 9.3 Hz, 1H), 8.07-8.02 (m,2H), 7.71 (t, J = 8.0 Hz, 1H), 7.56-7.48 (m, 7H), 7.34 (dt, J = 2.5, 9.5Hz, 1H), 7.02 (d, J = 8.5 Hz, 2H), 7.01-6.93 (m, 2H), 6.66 (t, J = 55.5Hz, 1H), 3.68 (s, 2H); MS: 652.0 (M − CO₂H)⁻.

Example 4

trans-2-(3-(3-(2-Cyanothioahen-3-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)phenyl)cyclopropane-1-carboxylicAcid (4)

A mixture of compound 2/4 (178 mg, 0.32 mmol) and LiOH.H₂O (67 mg, 1.62mmol) in THF (4.1 mL), MeOH (4.1 mL) and water (0.81 mL) was stirred atrt for 3 h, adjusted to pH=3 with 1N HCl, concentrated, diluted with EA(50 mL) and washed with water (3×5 mL) and brine (5 mL). The organiclayer was concentrated under reduced pressure, the residue was dissolvedin DMF (2.5 mL), filtrated and the filtrate was purified by prep-HPLC togive compound 4 as a white solid. ¹H-NMR (500 MHz, CD₃OD) δ: 8.90 (dd,J=8.5, 1.5 Hz, 1H), 8.60 (dd, J=4.8, 0.8 Hz, 1H), 7.79 (d, J=5.0 Hz,1H), 7.62 (dd, J=8.5, 4.5 Hz, 1H), 7.32-7.25 (m, 6H), 7.15-7.13 (m, 1H),6.95 (d, J=5.0 Hz, 1H), 6.76 (s, 1H), 2.39-2.38 (m, 4H), 1.77-1.73 (m,1H), 1.55-1.51 (m, 1H), 1.25 (br s, 1H); MS: 540.1 (M+1)⁺.

Example 4/1 to 4/3

The following Examples were prepared similar as described for Example 4using the appropriate starting material.

# starting material structure analytical data 4/1

¹H-NMR (500 MHz, CD₃OD) δ: 9.84 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.03(d, J = 6.0 Hz, 1H), 7.87 (d, J = 5.0 Hz, 1H), 7.34-7.28 (m, 6H), 7.12(d, J = 6.0 Hz, 1H), 6.99 (d, J = 5.0 Hz, 1H), 6.71 (s, 1H), 2.42-2.36(m, 4H), 1.76- 1.73 (m, 1H), 1.54-1.51 (m, 1H), 1.23 (br s, 1H); MS:540.1 (M + 1)⁺. 4/2

¹H-NMR (500 MHz, CD₃OD) δ: 8.51 (dd, J = 1.5, 5.0 Hz, 1H), 7.87 (dd, J =1.5, 8.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H),7.41 (dd, J = 5.3, 7.7 Hz, 1H), 7.34-7.26 (m, 4H), 7.21 (dd, J = 7.5,1.5 Hz 1H), 7.00 (s, 1H), 6.89 (d, J = 5.0 Hz, 1H), 2.47-2.44 (m, 1H),2.40 (s, 3H), 1.80-1.78 (m, 1H), 1.56-1.52 (m, 1H), 1.30-1.29 (m, 1H);MS: 540.0 (M + 1) ⁺. 4/3

¹H-NMR (500 MHz, DMSO- d₆) δ: 7.91 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 5.5Hz, 1H), 7.61-7.60 (m, 1H), 7.38-7.32 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H),6.81 (d, J = 4.5 Hz, 1H), 6.53-6.50 (m, 2H), 6.13 (d, J = 1.5 Hz, 1H),3.90 (t, J = 7.8 Hz, 2H), 3.76 (t, J = 6.3 Hz, 2H), 3.53-3.49 (m, 1H),2.35 (s, 3H); MS: 560.0 (M + 1)⁺.

Example 5

2-((5-(3-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)phenyl)pyridin-3-yl)sulfonyl)aceticAcid (5)

To a mixture of compound 2/8 (110 mg, 0.17 mmol) in MeOH (2 mL) and THF(1 mL) was added LiOH (2M, 0.3 mL) and the mixture was stirred at rt for1 h. The mixture was neutralized with 1N HCl and extracted with EA (3×).The combined organic layer was washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC to give compound 5 as awhite solid. ¹H-NMR (500 MHz, CD₃OD) δ:9.09 (d, J=2.0 Hz, 1H), 9.03 (d,J=2.0 Hz, 1H), 8.44-8.42 (m, 2H), 7.85-7.80 (m, 2H), 7.57-7.39 (m, 6H),7.33 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.06 (d, J=4.5 Hz, 1H),4.54 (s, 2H), 2.29 (s, 3H); MS: 554.1 (M+1)⁺.

Example 5/1 to 5/10

The following Examples were prepared similar as described for Example 5using the appropriate starting material.

# starting material structure analytical data 5/1

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.30 (br s, 1H), 8.30 (d, J = 8.5 Hz, 1H),8.05-8.00 (m, 2H), 7.92-7.86 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H),7.55-7.51 (m, 3H), 7.42-7.28 (m, 7H), 7.08 (d, J = 5.5 Hz, 1H), 4.96 (s,2H), 4.61 (s, 2H), 2.26 (s, 3H); MS: 699.8 (M + 18)⁺. 5/2

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.43 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H),8.01 (d, J = 5.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.38-7.22 (m, 9H),6.98-6.95 (m, 2H), 2.32 (s, 3H), 2.14 (s, 6H); MS: 562.8 (M − 1)⁻. 5/3

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.05 (s, 1H), 8.31 (dd, J = 9.2, 4.4 Hz,1H), 8.04-8.02 (m, 3H), 7.80 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.3 Hz,2H), 7.56-7.47 (m, 2H), 7.44-7.33 (m, 3H), 7.30-7.26 (m, 3H), 7.19 (dd,J = 8.6, 2.5 Hz, 1H), 7.07 (d, J = 5.1 Hz, 1H), 2.25 (s, 3H); MS: m/z590.6 (M − 1)⁻. 5/4

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.91 (br s, 1H), 8.27 (dd, J = 9.3, 4.8Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.45-7.33 (m, 7H), 7.22-7.17 (m, 3H),6.97 (d, J = 5.0 Hz, 1H), 2.33 (s, 3H), 1.48 (s, 6H); MS: 583.1 (M +1)⁺. 5/5

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.85 (d, J =5.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.57-7.50 (m, 2H), 7.39 (d, J =8.0 Hz, 2H), 7.32-7.23 (m, 6H), 7.07 (dd, J = 8.5, 2.5 Hz, 1H), 7.02 (d,J = 5.0 Hz, 1H), 6.90 (dd, J = 7.3, 1.8 Hz, 1H), 2.33 (s, 3H); MS: 609.9(M + 1)⁺. 5/6

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.73 (d, J = 5.5 Hz, 1H), 8.30 (dd, J =9.3, 4.3 Hz, 1H), 8.08- 8.04 (m, 5H), 7.92 (s, 1H), 7.48-7.40 (m, 3H),7.33-7.30 (m, 3H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 7.12 (d, J = 5.0 Hz,1H), 2.29 (s, 3H); MS: 594.1 (M + 1)⁺. 5/7

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 9.0, 4.5 Hz, 1H), 7.99 (d, J= 4.5 Hz, 1H), 7.61 (dd, J = 6.8, 2.3 Hz, 2H), 7.50 (dd, J = 6.8, 1.8Hz, 2H), 7.39-7.35 (m, 1H), 7.16-7.12 (m, 2H), 6.95 (d, J = 5.0 Hz, 1H),6.54 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 8.3, 1.8 Hz, 1H), 6.23 (s, 1H),3.89 (t, J = 7.8 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 3.48-3.43 (m, 1H);MS: 589.6 (M − 1)⁻. 5/8

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.32- 8.27 (m, 2H), 7.99 (d, J = 5.0 Hz,1H), 7.68 (dd, J = 8.8, 2.8 Hz, 1H), 7.39- 7.35 (m, 1H), 7.17- 7.13 (m,2H), 6.96- 6.91 (m, 2H), 6.55 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 8.0,2.0 Hz, 1H), 6.23 (s, 1H), 3.90-3.87 (m, 5H), 3.79 (t, J = 6.5 Hz, 2H),3.46-3.43 (m, 1H); MS: 586.7 (M − 1)⁻. 5/9

¹H-NMR (500 MHz, CD₃OD) δ: 8.41- 8.38 (m, 1H), 7.80 (d, J = 5.0 Hz, 1H)7.34-7.21 (m, 7H), 7.09 (d, J = 7.0 Hz, 1H), 7.04-7.02 (m, 1H), 6.97 (s,1H), 6.90 (d, J = 5.0 Hz, 1H), 3.11-3.07 (m, 1H), 2.96-2.94 (m, 1H),2.79-2.74 (m, 1H), 2.50-2.44 (m, 1H), 2.36 (s, 3H), 2.08-1.98 (m, 2H),1.87-1.82 (m, 1H), 1.59-1.51 (m, 1H), 0.86 (d, J = 6.0 Hz, 3H); MS:614.0 (M + 1)⁺. 5/10

¹H-NMR (500 MHz, CD₃OD) δ: 8.53 (dd, J = 9.2, 4.3 Hz, 1H), 8.12 (s, 1H),8.06-8.04 (m, 1H), 7.99-7.97 (m, 1H), 7.70-7.14 (m, 13H), 6.77 (t, J =55.5 Hz, 1H), 4.37-4.27 (m, 1H), 3.78-3.36 (m, 3H), 3.24-3.20 (m, 1H);MS: 704.1 (M + 1)⁺.

Example 6

3′-(3-(2-Cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-N-hydroxy-[1,1′-biphenyl]-4-carboxamide(6)

To a mixture of compound 5/3 (120 mg, 0.20 mmol) in DMF (5 mL) was addedhydroxylamine hydrochloride (27 mg, 0.40 mmol), HATU (114 mg, 0.30 mmol)and DIPEA (103 mg, 0.80 mmol) and the mixture was stirred at rtovernight, diluted with EA (40 mL) and washed with H₂O (30 mL), 1N HCl(20 mL) and brine (30 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC to give compound 6 as awhite solid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 10.69 (br s, 1H), 9.15 (br s,1H), 8.31 (dd, J=9.3, 4.3 Hz, 1H), 8.02 (d, J=5.0 Hz, 1H), 7.86 (d,J=8.5 Hz, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.50-7.47(m, 2H), 7.41-7.25 (m, 6H), 7.19 (dd, J=8.5, 2.5 Hz, 1H), 7.07 (d, J=5.0Hz, 1H), 2.25 (s, 3H); MS: 605.8 (M−1)⁻.

Example 6/1 to 6/3

The following Example was prepared similar as described for Example 6using the appropriate starting material.

# starting material structure analytical data 6/1

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.39 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 5.5Hz, 1H), 7.53-7.23 (m, 9H), 7.04-7.01 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H),2.43-2.38 (m, 1H), 1.76-1.72 (m, 1H), 1.54-1.50 (m, 1H), 1.25-1.20 (m,1H); MS: 574.1 (M + 1)⁺. 6/2

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J = 9.0, 4.0 Hz, 1H), 8.04-7.96(m, 4H), 7.78 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50-7.36(m, 6H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 8.0, 2.5 Hz, 1H), 7.06(d, J = 5.0 Hz, 1H), 2.25 (s, 3H); MS: 589.8 (M − 1)⁻. 6/3

¹H-NMR (400 MHz, CD₃OD) δ: 8.43 (dd, J = 4.4, 9.2 Hz, 1H), 8.05 (d, J =7.6 Hz, 2H), 7.96 (d, J = 1.2 Hz, 1H), 7.84 (dd, J = 1.8, 7.8 Hz, 1H),7.71 (t, J = 8.0 Hz, 1H), 7.54-7.30 (m, 9H), 7.09 (s, 1H), 6.94 (dd, J =2.4, 8.4 Hz, 1H), 6.67 (t, J = 55.4 Hz, 1H), 4.03 (s, 2H), 1.51 (s, 9H);MS: 793.1 (M − 1)⁻.

Example 7

Methyl4-(3-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)phenyl)-2,2-dimethylbut-3-ynoate(7)

To a solution of compound 1 (234 mg, 0.52 mmol) in Et₃N (1.5 mL) wasadded Pd(PPh₃)₄ (47 mg), CuI (80 mg), PPh₃ (11 mg) and methyl2,2-dimethylbut-3-ynoate (78 mg, 0.62 mmol). The mixture was stirred at60° C. under N₂ for 4 h, cooled, filtered, concentrated and purified byFCC (PE:EA=8:1) to give compound 7 as a yellow solid.

Example 8

3-(5-Fluoro-2-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-3-yl)-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile(8)

To a solution of compound 1 (250 mg, 0.45 mmol) in dioxane (20 mL) wasadded (3-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid (116 mg,0.50 mmol), Cs₂CO₃ (293 mg, 0.90 mmol) and Pd(PPh₃)₄ (52 mg, 50 μmol).The mixture was stirred at 100° C. overnight under N₂, cooled, filtered,concentrated and purified by prep-HPLC to give compound 8 as a whitesolid. ¹H-NMR (500 MHz, CD₃D) δ: 8.43 (dd, J=4.5, 9.5 Hz, 1H), 7.82 (d,J=5.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.47-7.41 (m, 8H), 7.31-7.15 (m,7H), 7.06 (dd, J=2.5, 8.5 Hz, 1H), 6.96 (d, J=5.0 Hz, 1H), 3.61 (s, 2H),2.61-2.48 (m, 8H), 2.31 (s, 3H), 2.27 (s, 3H); MS: 661.0 (M+1)⁺.

Example 8/1 to 8/8

The following Example was prepared similar as described for Example 8using the appropriate starting materials.

# starting material(s) structure analytical data 8/1

¹H-NMR (500 MHz, DMSO- d₆) δ: 8.31 (dd, J = 4.5, 9.0 Hz, 1H), 8.02 (d, J= 5.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.49-7.35 (m, 9H), 7.27-7.17(m, 4H), 7.06 (d, J = 5.0 Hz, 1H), 3.43 (s, 2H), 2.25 (s, 3H), 2.17 (s,6H); MS: 606.0 (M + 1)⁺. 8/2

8/3

¹H-NMR (500 MHz, CD₃OD) δ: 8.60 (d, J = 5.9 Hz, 1H), 8.43 (d, J = 6.0Hz, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.99- 7.97 (m, 1H), 7.76-7.08 (m,13H), 6.74 (t, J = 55.5 Hz, 1H), 4.65-4.56 (m, 1H), 4.53- 4.49 (m, 1H),4.41-4.37 (m, 1H), 4.30-4.26 (m, 1H), 3.90- 3.78 (m, 1H); MS: 671.1 (M +1)⁺. 8/4

8/5

8/6

8/7

¹H-NMR (500 MHz, CD₃OD) δ: 8.81 (dd, J = 8.5, 1.5 Hz, 1H), 8.56 (dd, J =4.8, 1.3 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H),7.77 (d, J = 7.5 Hz, 1H), 7.65-7.04 (m, 13H), 6.70 (t, J = 55.5 Hz, 1H);MS: 640.2 (M + 1)⁺. 8/8

¹H-NMR (400 MHz, CD₃OD) δ: 8.42 (dd, J = 9.4, 4.2 Hz, 1H), 8.05-8.03 (m,3H), 7.96 (dd, J = 8.2, 1.8 Hz, 1H), 7.70 (dd, J = 8.4, 7.6 Hz, 1H),7.51-7.44 (m, 8H), 7.32 (td, J = 9.2, 2.4 Hz, 1H), 6.97 (s, 1H), 6.94(dd, J = 8.4, 2.4 Hz, 1H), 6.62 (t, J = 55.4 Hz, 1H), 2.00 (s, 3H); MS:757.0 (M − 1)⁻.

Example 9

Methyl3′-(3-(2,6-bis(difluoromethyl)phenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-2-chloro-[1,1′-biphenyl]-4-carboxylate(9)

To a solution of compound 1/55 (180 mg, 0.26 mmol) in DCM (10.0 mL) wasadded DAST (209 mg, 1.30 mmol) and the mixture was stirred at rtovernight, poured into EA (200 mL) and washed with H₂O (2×20 mL) andbrine (20 mL). The organic layer was dried over Na₂SO₄, concentrated andpurified by prep-TLC (EA:PE=1:3) to give compound 9 as a colorless oil.

Example 9/1

The following Example was prepared similar as described for Example 9using the appropriate starting material.

# starting material structure 9/1

Example 10

2-(2-Chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicAcid (10)

To a solution of compound 3/48 (100 mg, 0.20 mmol) in DMF (10 mL) wasadded EDCl (100 mg, 0.50 mmol), DMAP (60 mg, 0.50 mmol) and2-aminoethane-1-sulfonic acid (22 mg, 0.20 mmol). The mixture wasstirred at rt for 12 h, diluted with water (100 mL) and extracted withEA (3×100 mL). The combined organic layer was washed with brine (50 mL),concentrated and purified by FCC (PE:EA=1:4) to give compound 10 as awhite solid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.68 (t, J=5.3 Hz, 1H), 8.29(dd, J=4.5, 9.0 Hz, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H),7.81 (dd, J=1.8, 8.3 Hz, 1H), 7.54-7.17 (m, 10H), 7.03-7.01 (m, 2H),3.56-3.52 (m, 2H), 2.70-2.67 (m, 2H), 2.21 (s, 3H); MS: 731.9 (M−1)⁻.

Example 10/1 to 1014

The following Examples were prepared similar as described for Example 10using the appropriate starting material.

# starting material structure analytical data 10/1

¹H-NMR (500 MHz, CD₃OD) δ: 8.45- 8.43 (m, 1H), 8.07 (br s, 2H), 7.94 (d,J = 2.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.78 (t, J = 7.8 Hz,1H), 7.55-7.43 (m, 7H), 7.36-7.28 (m, 2H), 7.04 (s, 1H), 6.95 (dd, J =8.5, 2.5 Hz, 1H), 6.68 (t, J = 55.5 Hz, 1H), 3.84 (t, J = 6.5 Hz, 2H),3.13 (t, J = 6.5 Hz, 2H); MS: 786.9 (M − 1)⁻. 10/2

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.3, 4.3 Hz, 1H), 8.06 (br s,2H), 7.72 (t, J = 7.8 Hz, 1H), 7.59- 7.47 (m, 9H), 7.35- 7.32 (m, 2H),7.02- 6.58 (m, 3H), 3.97- 3.77 (m, 2H), 3.24- 3.10 (m, 5H); MS: 801.0 (M− 1)⁻. 10/3

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 7.97 (d, J =1.5 Hz, 1H), 7.85- 7.81 (m, 2H), 7.56- 7.49 (m, 6H), 7.44 (d, J = 7.0Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.31 (td, J = 9.0, 2.5 Hz, 1H),7.09-7.06 (m, 2H), 6.98 (d, J = 5.0 Hz, 1H), 6.71 (t, J = 55.5 Hz, 1H),3.84 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H); MS: 768.0 (M − 1)⁻.10/4

¹H-NMR (400 MHz, CD₃OD) δ: 8.37 (dd, J = 9.2, 4.4 Hz, 1H), 7.59 (d, J =8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40-7.35 (m, 3H), 7.26-7.14 (m,4H), 6.95-6.64 (m, 3H), 3.69-3.61 (m, 2H), 3.00 (t, J = 6.6 Hz, 2H),2.33-2.28 (m, 1H), 1.64 (br s, 1H), 1.47-1.42 (m, 1H), 1.06 (br s, 1H);MS: 735.0 and 737.0 (M − 1)⁻.

Example 11

2-Chloro-3′-(3-(2-cyanophenyl)-5-fluoro-1-tosyl-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicacid (11)

To a solution of compound 1/32 (165 mg, 0.26 mmol) in HCl/dioxane (4N, 5mL) was added H₂O (0.5 mL). The mixture was stirred at 90° C. overnight,cooled, concentrated, diluted with water and extracted with EA (3×). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC to give compound 11 asa white solid. ¹H-NMR (500 MHz, DMSO-d) δ: 13.36 (br s, 1H), 8.28 (dd,J=4.5, 9.5 Hz, 1H), 7.97-7.94 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.66 (t,J=7.5 Hz, 1H), 7.55-7.31 (m, 9H), 7.24 (d, J=8.5 Hz, 2H), 7.02-7.00 (m,2H), 2.21 (s, 3H); MS: 619.0 (M−1)⁻.

Example 11/1 to 11/69

The following Examples were prepared similar as described for Example 11using the appropriate starting material.

# starting material structure analytical data 11/1

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (d, J =1.0 Hz, 1H), 8.02 (dd, J = 1.8, 8.3 Hz, 1H), 7.69-7.64 (m, 1H),7.49-7.26 (m, 8H), 7.18-1.15 (m, 3H), 7.02 (s, 1H), 6.97 (dd, J = 2.5,8.5 Hz, 1H), 2.25 (s, 3H); MS: 637.0 (M − 1)⁻. 11/2

¹H-NMR (500 MHz, CD₃OD) δ: 8.39 (dd, J = 9.3, 4.3 Hz, 1H), 8.05 (d, J =1.5 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 1H), 7.51-7.43 (m, 4H), 7.39 (d,J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.28-6.98 (m, 7H), 6.88 (dd,J = 8.5, 2.5 Hz, 1H), 2.51 (s, 3H), 2.24 (s, 3H); MS: 633.0 (M − 1)⁻.11/3

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (dd, J = 9.0, 4.5 Hz, 1H), 8.07 (d, J =1.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.57-7.54 (m, 1H),7.48-7.44 (m, 3H), 7.37 (d, J = 7.5 Hz, 1H), 7.27- 7.14 (m, 6H), 7.03(s, 1H), 6.88 (dd, J = 8.3, 2.8 Hz, 1H), 6.83 (br s, 1H), 3.95 (s, 3H),2.24 (s, 3H); MS: 649.0 (M − 1)⁻. 11/4

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (dd, J = 9.3, 4.3 Hz, 1H), 8.07 (d, J =1.5 Hz, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.63-7.54 (m, 1H),7.45-7.42 (m, 4H), 7.36 (d, J = 8.0 Hz, 1H), 7.30- 7.14 (m, 6H), 7.02(s, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H); MS:633.0 (M − 1)⁻. 11/5

¹H-NMR (500 MHz, CD₃OD) δ: 8.39 (dd, J = 9.0, 4.5 Hz, 1H), 8.07 (d, J =2.0 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H),7.46- 7.44 (m, 3H), 7.36 (d, J = 8.5 Hz, 1H), 7.33-7.14 (m, 7H), 7.03(s, 1H), 6.89 (dd, J = 8.3, 2.8 Hz, 1H), 2.35 (s, 3H), 2.24 (s, 3H); MS:633.0 (M − 1)⁻. 11/6

¹H-NMR (500 MHz, CD₃OD) δ: 8.40 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (s, 1H),8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.58- 7.15 (m, 13H), 6.71 (dd, J = 8.0,2.5 Hz, 1H), 2.25 (s, 3H), 1.90 (s, 3H); MS: 633.0 (M − 1)⁻. 11/7

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (dd, J = 9.0, 4.5 Hz, 1H), 8.03 (d, J =7.0 Hz, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.57-7.44 (m, 5H), 7.38 (d, J =8.5 Hz, 2H), 7.30 (dt, J = 2.7, 9.2 Hz, 1H), 7.21 (d, J = 10.5 Hz, 1H),7.15 (s, 1H), 7.07 (dd, J = 8.5, 2.5 Hz, 1H), 6.99 (d, J = 5.5 Hz, 1H),5.35 (d, J = 47.0 Hz, 2H); MS: 660.9 (M − 1)⁻. 11/8

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J =6.5 Hz, 1H), 7.86 (d, J = 5.0 Hz, 1H), 7.58-7.49 (m, 6H), 7.43 (d, J =7.5 Hz, 1H), 7.31 (td, J = 9.0, 2.5 Hz, 1H), 7.22 (d, J = 10.5 Hz, 1H),7.16 (s, 1H), 7.09 (dd, J = 2.5, 8.5 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H),6.73 (t, J = 55.5 Hz, 1H); MS: 678.9 (M − 1)⁻. 11/9

¹H-NMR (500 MHz, CD₃OD) δ: 9.33 (s, 1H), 8.46 (dd, J = 9.3, 4.3 Hz, 1H),8.04 (d, J = 6.5 Hz, 1H), 7.61-7.50 (m, 6H), 7.41 (d, J = 8.0 Hz, 1H),7.33 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 11.0 Hz, 1H), 7.21- 7.18 (m, 2H),6.73 (t, J = 55.5 Hz, 1H); MS: 679.9 (M − 1)⁻. 11/ 10

¹H-NMR (500 MHz, CD₃OD) δ: 8.72 (d, J = 4.5 Hz, 1H), 8.55 (br s, 1H),8.44 (dd, J = 4.3, 9.3 Hz, 1H), 8.01 (d, J = 6.5 Hz, 1H), 7.78 (d, J =5.0 Hz, 1H), 7.60-7.04 (m, 11H), 6.73 (t, J = 55.5 Hz, 1H); MS: 673.9 (M− 1)⁻. 11/ 11

¹H-NMR (500 MHz, CD₃OD) δ: 8.90 (d, J = 2.5 Hz, 1H), 8.71 (d, J = 2.5Hz, 1H), 8.47 (dd, J = 9.5, 4.5 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.78-7.18 (m, 11H), 6.73 (t, J = 55.5 Hz, 1H); MS: 674.9 (M − 1)⁻. 11/ 12

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 4.3, 9.3 Hz, 1H), 8.08-8.00 (m,4H), 7.72 (t, J = 7.8 Hz, 1H), 7.55-7.32 (m, 9H), 7.08 (s, 1H), 6.95(dd, J = 2.5, 8.5 Hz, 1H), 6.68 (t, J = 55.5 Hz, 1H); MS: 679.9 (M −1)⁻. 11/ 13

¹H-NMR (500 MHz, CD₃OD) δ: 8.39 (dd, J = 4.8, 9.3 Hz, 1H), 8.08 (d, J =1.5 Hz, 1H), 7.98 (dd, J = 1.5, 8.0 Hz, 1H), 7.56-7.25 (m, 12H), 7.21(s, 1H), 6.73 (t, J = 55.3 Hz, 1H), 6.68 (dd, J = 2.5, 8.5 Hz, 1H); MS:697.9 (M − 1)⁻. 11/ 14

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (dd, J = 4.2, 9.0 Hz, 1H), 8.07 (d, J =1.6 Hz, 1H), 7.94 (dd, J = 1.6, 8.0 Hz, 1H), 7.57-7.40 (m, 7H),7.29-7.15 (m, 4H), 7.04 (d, J = 8.4 Hz, 2H), 6.75 (t, J = 55.6 Hz, 1H),6.57 (d, J = 2.6, 8.2 Hz, 1H), 1.63 (s, 6H); MS: 658.0 (M − 1)⁻. 11/ 15

¹H-NMR (400 MHz, CD₃OD) δ: 8.44 (dd, J = 4.4, 9.2 Hz, 1H), 8.08 (d, J =1.6 Hz, 1H), 7.97 (dd, J = 1.4, 3.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H),7.73 (t, J = 7.8 Hz, 1H), 7.61-7.55 (m, 4H), 7.47-7.23 (m, 5H), 6.91 (s,1H), 6.77- 6.63 (m, 2H), 6.01 (t, J = 55.0 Hz, 2H); MS: 729.9 (M − 1)⁻.11/ 16

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.39 (s, 1H), 8.78 (d, J = 2.5 Hz, 1H),8.34 (dd, J = 9.0, 4.5 Hz, 1H), 8.12-7.93 (m, 5H) 7.57-7.55 (m, 2H),7.50-7.41 (m, 3H), 7.23-7.21 (m, 2H), 7.04-7.02 (m, 1H); MS: 679.6 (M −1)⁻. 11/ 17

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 8.04 (d, J= 5.1 Hz, 1H), 7.99-7.88 (m, 2H), 7.70-7.49 (m, 6H), 7.47-7.35 (m, 3H),7.20 (dd, J = 8.6, 2.6 Hz, 1H), 7.12-7.10 (m, 1H), 7.05-7.03 (m, 1H),7.01 (t, J = 55.0 Hz, 1H); MS: 660.9 (M − 1)⁻. 11/ 18

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 8.04 (d, J= 5.1 Hz, 1H), 7.99-7.88 (m, 2H), 7.58-7.45 (m, 4H), 7.45-7.35 (m, 3H),7.31 (t, J = 8.8 Hz, 2H), 7.19 (dd, J = 8.6, 2.6 Hz, 1H), 7.14 (s, 1H),7.03 (d, J = 4.9 Hz, 1H); MS: 628.9 (M − 1)⁻. 11/ 19

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.42 (s, 1H), 8.31 (dd, J = 9.2, 4.5 Hz,1H), 8.05-7.93 (m, 3H), 7.55-7.53 (m, 2H), 7.48-7.36 (m, 4H), 7.24-7.11(m, 4H), 7.05 (d, J = 4.8 Hz, 1H), 2.15 (s, 3H); MS: 642.9 (M − 1)⁻. 11/20

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.46 (s, 1H), 8.31- 8.28 (m, 1H), 8.05 (d,J = 5.1 Hz, 1H), 8.02-7.92 (m, 4H), 7.59-7.50 (m, 4H), 7.48-7.37 (m,3H), 7.22-7.20 (m, 1H), 7.12 (s, 1H), 7.04 (d, J = 5.0 Hz, 1H); MS:635.9 (M − 1)⁻. 11/ 21

¹H-NMR (400 MHz, CD₃OD) δ: 8.36 (dd, J = 9.2, 4.4 Hz, 1H), 8.07 (d, J =1.6 Hz, 1H), 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J = 5.0 Hz, 1H),7.52- 7.33 (m, 7H), 7.31- 7.22 (m, 2H), 7.12 (s, 1H), 6.91 (dd, J = 8.5,2.5 Hz, 1H), 6.82 (br s, 1H), 6.34 (t, J = 54.8 Hz, 1H); MS: 669.8 (M −1)⁻. 11/ 22

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (dd, J = 9.2, 4.3 Hz, 1H), 8.11 (d, J =1.3 Hz, 1H), 8.01 (d, J = 6.9 Hz, 1H), 7.70 (d, J = 4.0 Hz, 1H),7.57-7.24 (m, 10H), 6.85- 6.63 (m, 3H); MS: 703.9 (M − 1)⁻. 11/ 23

¹H-NMR (500 MHz, CD₃OD) δ: 8.78 (d, J = 4.6 Hz, 1H), 8.42 (dd, J = 9.2,4.3 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 8.01(dd, J = 8.0, 1.5 Hz, 1H), 7.70-7.06 (m, 11H), 6.79-6.77 (m, 1H), 6.76(t, J = 56.0, 1H); MS: 699.0 (M − 1)⁻. 11/ 24

¹H-NMR (400 MHz, CD₃OD) δ: 8.36 (dd, J = 9.1, 4.4 Hz, 1H), 8.07 (d, J =1.5 Hz, 1H), 7.97 (dd, J = 7.9, 1.6 Hz, 1H), 7.56-7.43 (m, 7H), 7.33 (d,J = 8.0 Hz, 1H), 7.25 (dt, J = 4.4, 8.8 Hz, 1H), 7.15 (s, 1H), 6.82-6.79(m, 1H), 6.73 (t, J = 55.2 Hz, 1H), 1.70 (s, 6H); MS: 650.1 (M + H)⁺.11/ 25

¹H-NMR (500 MHz, CD₃OD) δ: 8.37 (dd, J = 9.1, 4.3 Hz, 1H), 8.09 (d, J =1.4 Hz, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.68-6.89 (m, 11H),6.88-6.86 (m, 1H), 6.73 (t, J = 55.0 Hz, 1H): MS: 688.0 (M − 1)⁻. 11/ 26

¹H-NMR (500 MHz, CD₃OD) δ: 8.84 (dd, J = 5.0, 1.6 Hz, 1H), 8.45 (dd, J =9.2, 4.3 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 8.07 (s, 1H), 8.00 (d,J = 8.0 Hz, 1H), 7.82- 7.10 (m, 11H), 7.05 (dd, J = 8.4, 2.5 Hz, 1H),6.71 (t, J = 55.6 Hz, 1H); MS: 655.9 (M − 1)⁻. 11/ 27

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.28 (dd, J = 9.0, 4.5 Hz, 1H), 7.88 (d, J= 6.0 Hz, 1H), 7.76-7.36 (m, 12H), 7.12-6.90 (m, 4H), 3.82 (s, 3H); MS:684.9 (M − 1)⁻. 11/ 28

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.0, 4.0 Hz, 1H), 7.78 (d, J =7.5 Hz, 2H), 7.61- 7.39 (m, 10H), 7.30-7.26 (m, 2H), 6.95 (d, J = 8.5Hz, 1H), 6.90-6.87 (m, 1H), 6.70 (t, J = 55.5 Hz, 1H), 6.08 (d, J = 4.5Hz, 2H); MS: 665.0 (M − 1)⁻. 11/ 29

¹H-NMR (400 MHz, CD₃OD) δ: 8.40 (dd, J = 9.2, 4.4 Hz, 1H), 7.79-7.50 (m,10H), 7.35-7.17 (m, 6H), 6.88 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (t, J =55.6 Hz, 1H), 3.83 (s, 3H); MS: 651.0 (M − 1)⁻. 11/ 30

¹H-NMR (400 MHz, CD₃OD) δ: 8.43- 8.40 (m, 2H), 8.29 (dd, J = 8.2, 1.4Hz, 1H), 7.77-7.75 (m, 1H), 7.67-7.26 (m, 13H), 6.91 (dd, J = 2.8, 8.4Hz, 1H), 6.74 (t, J = 55.6 Hz, 1H); MS: 646.0 (M − 1)⁻. 11/ 31

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (dd, J = 9.2, 4.4 Hz, 1H), 7.87 (dd, J =1.6, 8.0 Hz, 1H), 7.76 (dd, J = 1.4, 11.0 Hz, Hz, 1H), 7.65-7.26 (m,13H), 6.89 (dd, J = 2.4, 8.4 Hz, 1H), 6.72 (t, J = 55.6 Hz, 1H); MS:639.0 (M − 1)⁻. 11/ 32

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (dd, J = 9.2, 4.4 Hz, 1H), 7.83 (d, J =8.4 Hz, 1H), 7.78- 6.55 (m, 16H); MS: 670.9 (M − 1)⁻. 11/ 33

¹H-NMR (500 MHz, MeOD) δ: 8.40 (dd, J = 9.3, 4.3 Hz, 1H), 8.07 (d, J =2.0 Hz, 1H), 7.99 (dd, J = 7.8, 1.8 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H),7.64 (t, J = 7.5 Hz, 1H), 7.56-7.44 (m, 8H), 7.35-7.26 (m, 3H), 7.09 (brs, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.70 (t, J = 55.5 Hz, 1H); MS:670.9 (M − 1)⁻. 11/ 34

¹H-NMR (400 MHz, MeOD) δ: 8.42 (dd, J = 9.4, 4.2 Hz, 1H), 8.06 (d, J =1.6 Hz, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.64-7.41 (m, 10H),7.34-7.28 (m, 2H), 7.05 (br s, 1H), 6.90 (dd, J = 8.2, 2.6 Hz, 1H), 6.70(t, J = 55.4 Hz, 1H); MS: 670.9 (M − 1)⁻. 11/ 35

¹H-NMR (500 MHz, MeOD) δ: 8.37 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (d, J =1.0 Hz, 1H), 7.99 (dd, J = 7.5, 1.5 Hz, 1H), 7.56-7.23 (m, 12H), 7.10(br s, 1H), 6.76 (dd, J = 1.8, 8.3 Hz, 1H), 6.72 (t, J = 55.5 Hz, 1H),3.59 (s, 3H); MS: 670.9 (M − 1)⁻. 11/ 36

¹H-NMR (500 MHz, MeOD) δ: 8.41 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (d, J =1.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.60-7.15 (m, 13H),6.82-6.60 (m, 2H), 1.88 (s, 3H); MS: 670.9 (M − 1)⁻. 11/ 37

¹H-NMR (400 MHz, MeOD) δ: 8.68 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 9.2,4.0 Hz, 1H), 8.09- 7.98 (m, 5H), 7.83 (d, J = 8.4 Hz, 1H), 7.74 (t, J =7.8 Hz, 1H), 7.55-7.38 (m, 5H), 7.20 (s, 1H), 6.97 (dd, J = 8.2, 2.6 Hz,1H); MS: 698.9 (M − 1)⁻. 11/ 38

¹H-NMR (500 MHz, MeOD) δ: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 8.09 (d, J =2.0 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz 1H), 7.59-7.25 (m, 12H), 7.21 (brs, 1H), 6.77 (t, J = 55.5 Hz, 1H), 6.59 (dd, J = 8.0, 2.5 Hz, 1H), 5.90(t, J = 55.5 Hz, 1H), 1.70 (s, 3H); MS: 694.0 (M − 1)⁻. C11/ 39

¹H-NMR (400 MHz, CD₃OD) δ: 8.40 (dd, J = 9.2, 4.4 Hz, 1H), 8.07 (d, J =1.6 Hz, 1H), 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.56-7.45 (m, 7H),7.34-7.21 (m, 5H), 7.14-7.11 (m, 4H), 6.73 (t, J = 55.6 Hz, 1H); MS:630.0 (M − 1)⁻. 11/ 40

¹H-NMR (500 MHz, CD₃OD) δ: 8.41 (dd, J = 9.0, 4.5 Hz, 1H), 8.19 (dd, J =1.0, 4.5 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 8.01 (dd, J = 7.8, 1.8 Hz,1H), 7.56-7.46 (m, 9H), 7.39 (d, J = 8.0 Hz, 1H), 7.29- 7.25 (m, 1H),7.14 (br s, 1H), 7.00 (dd, J = 9.0, 2.5 Hz, 1H), 6.74 (t, J = 55.5 Hz,1H), 3.50 (s, 3H); MS: 663.0 (M + 1)⁺. 11/ 41

¹H-NMR (400 MHz, CD₃OD) δ: 8.44- 8.40 (m, 2H), 8.07 (d, J = 1.6 Hz, 1H),8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.57-7.25 (m,10H), 7.14 (br s, 1H), 6.98 (dd, J = 8.6, 2.6 Hz, 1H), 6.73 (t, J = 55.6Hz, 1H), 6.51 (t, J = 72.6 Hz, 1H); MS: 699.0 (M + 1)⁺. 11/ 42

¹H-NMR (400 MHz, CD₃OD) δ: 8.32 (dd, J = 9.0, 4.6 Hz, 1H), 8.16 (d, J =1.6 Hz, 1H), 8.07 (dd, J = 7.8, 1.4 Hz, 1H), 7.62-7.22 (m, 10H), 7.15(dd, J = 8.2, 2.6 Hz, 1H), 6.70 (t, J = 55.6 Hz, 1H), 2.43-2.16 (m, 3H),1.92-1.43 (m, 5H); MS: 659.0 (M − 1)⁻. 11/ 43

¹H-NMR (500 MHz, CD₃OD) δ: 8.67 (br s, 1H), 8.51-8.48 (m, 1H), 8.00-7.93 (m, 2H), 7.75 (d, J = 9.5 Hz, 1H), 7.63-7.00 (m, 13H), 6.73 (t, J =55.3 Hz, 1H); MS: 671.0 (M − 1)⁻. 11/ 44

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (dd, J = 9.1, 4.3 Hz, 1H), 8.08 (d, J =1.5 Hz, 1H), 7.99 (dd, J = 7.8, 1.4 Hz, 1H), 7.56-7.415 (m, 7H), 7.35(d, J = 8.0 Hz, 1H), 7.27- 7.22 (m, 1H), 7.16 (s, 1H), 7.07 (dd, J =8.5, 2.5 Hz, 1H), 6.84-6.60 (m, 4H), 5.65 (s, 2H); MS: 674.0 (M − 1)⁻.11/ 45

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 9.3, 4.3 Hz, 1H), 8.01 (d, J =1.5 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H),7.59- 7.55 (m, 4H), 7.49- 7.28 (m, 7H), 7.07-7.05 (m, 2H), 6.72 (t, J =55.5 Hz, 1H); MS: 671.9 (M − 1)⁻. 11/ 46

¹H-NMR (500 MHz, CD₃OD) δ: 8.43- 8.40 (m, 2H), 8.22- 7.97 (m, 3H),7.54-6.72 (m, 13H), 3.86 (s, 3H); MS: 725.0 (M − 1)⁻. 11/ 47

¹H-NMR (500 MHz, CD₃OD) δ: 8.34 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (s, 1H),8.01 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.0, 6.5 Hz, 1H), 7.59-7.42 (m,8H), 7.23-7.18 (m, 3H), 7.00 (dd, J = 2.3, 8.8 Hz, 1H), 6.72 (t, J =55.5 Hz, 1H), 6.27-6.25 (m, 1H), 3.57 (s, 3H); MS: 661.0 (M − 1)⁻. C11/48

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 8.06 (d, J =1.5 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 1H), 7.64-7.46 (m, 11H), 7.36(d, J = 7.5 Hz, 1H), 7.31- 7.26 (m, 1H), 7.18 (dd, J = 8.8, 2.8 Hz, 1H),7.10 (s, 1H), 6.73 (t, J = 55.8 Hz, 1H); MS: 654.9 (M − 1)⁻. 11/ 49

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.52 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H),7.94-7.88 (m, 3H), 7.71-7.32 (m, 12H), 7.14-6.86 (m, 2H); MS: 638.0 (M −1)⁻. 11/ 50

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.36 (dd, J = 9.5, 4.0 Hz, 1H), 8.25 (d, J= 8.0 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.79 (t, J = 7.8 Hz, 2H), 7.68(d, J = 8.0 Hz, 2H), 7.60-7.56 (m, 4H), 7.50-7.40 (m, 3H), 7.26 (dd, J =2.5, 8.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 55.3 Hz, 1H);MS: 646.0 (M − 1)⁻. 11/ 51

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 9.5, 4.0 Hz, 1H), 8.06 (br s,2H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.78-7.63 (m, 3H), 7.56-7.29 (m,9H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H), 6.69 (t, J = 55.8 Hz, 1H); MS:664.0 (M − 1)⁻. 11/ 52

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 9.0, 4.5 Hz, 1H), 8.07 (br s,2H), 7.77-7,64 (m, 3H), 7.57-7.48 (m, 5H), 7.41-7.29 (m, 3H), 7.21-7.18(m, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 6.71 (t, J = 55.8 Hz, 1H); MS:682.0 (M − 1)⁻. 11/ 53

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.0, 4.0 Hz, 1H), 8.07-8.03 (m,2H), 7.72 (t, J = 8.3 Hz, 1H), 7.66-7.50 (m, 9H), 7.33 (td, J = 9.0, 2.5Hz, 1H), 7.00 (s, 1H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 6.68 (t, J = 55.5Hz, 1H); MS: 682.0 (M − 1)⁻. 11/ 54

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.3, 4.8 Hz, 1H), 8.12-8.02 m,2H), 7.77-7.72 (m, 1H), 7.62-7.51 (m, 7H), 7.35 (td, J = 9.3, 2.8 Hz,1H), 7.06 (s, 1H), 6.97 (dd, J = 8.0, 2.5 Hz, 1H), 6.71 (t, J = 55.5 Hz,1H); MS: 737.1 (M + 18)⁺. 11/ 55

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 9.5, 4.0 Hz, 1H), 8.09-8.04 (m,3H), 8.00 (dd, J = 1.5, 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.49-7.44 (m, 3H), 7.38- 7.29 (m, 6H), 7.05 (d, J = 1.0 Hz, 1H), 6.95 (dd, J= 8.5, 2.5 Hz, 1H); MS: 663.9/666.0 (M − 1)⁻. 11/ 56

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (d, J = 8.5 Hz, 1H), 8.09-8.04 (m, 3H),7.98 (dd, J = 7.5, 1.5 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.58-7.47 (m,8H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19 (d, J =7.5 Hz, 1H), 7.07 (s, 1H), 6.66 (t, J = 55.5 Hz, 1H); MS: 661.9 (M −1)⁻. 11/ 57

¹H-NMR (400 MHz, CD₃OD) δ: 8.60 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 4.4,9.2 Hz, 1H), 8.10 (s, 1H), 8.03-7.31 (m, 9H), 7.21 (s, 1H), 7.09 (dd, J= 2.8, 8.4 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.65 (t, J = 54.6 Hz, 1H);MS: 663.8 (M + 1)⁺. 11/ 58

¹H-NMR (500 MHz, CD₃OD) δ: 8.45 (dd, J = 9.3, 4.3 Hz, 1H), 8.07-7.98 (m,2H), 7.69 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.43 (d, J =8.0 Hz, 2H), 7.37-7.31 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.79 (t, J = 55.8 Hz, 1H), 1.90- 1.87(m, 6H), 1.70-1.67 (m, 6H); MS: 678.0 (M − 1)⁻. 11/ 59

¹H-NMR (500 MHz, CD₃OD) δ: 8.46 (dd, J = 9.2, 4.3 Hz, 1H), 8.05 (d, J =7.9 Hz, 2H), 7.75- 7.62 (m, 4H), 7.52 (q, J = 8.6 Hz, 4H), 7.47-7.28 (m,5H), 7.21 (d, J = 7.8 Hz, 1H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 6.67 (t,J = 55.6 Hz, 1H), 1.79 (s, 3H); MS: 690.0 (M − 1)⁻. 11/ 60

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.5, 4.3 Hz, 1H), 8.06 (br s,2H), 7.75-7.70 (m, 2H), 7.62-7.59 (m, 1H), 7.52-7.48 (m, 4H), 7.45-7.43(m, 2H), 7.35-7.31 (m, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.98- 6.93 (m,2H), 6.64 (t, J = 55.6 Hz, 1H), 1.77 (s, 3H); MS: 724.0 (M − 1)⁻. 11/ 61

¹H-NMR (500 MHz, CD₃OD) δ: 8.45- 8.42 (m, 1H), 8.02 (br s, 2H), 7.68 (t,J = 7.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H),7.37- 7.13 (m, 4H), 6.98- 6.60 (m, 3H), 2.65 (s, 1H), 2.50-2.45 (m, 1H),2.17-2.14 (m, 2H), 1.71-1.11 (m, 6H); MS: 652.0 (M − 1)⁻. 11/ 62

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.2, 4.3 Hz, 1H), 8.04-8.00 (m,2H), 7.69 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.47 (d, J =8.3 Hz, 2H), 7.32 (td, J = 9.1, 2.5 Hz, 1H), 7.29-7.16 (m, 2H),7.09-7.07 (m, 1H), 7.01-6.61 (m, 3H), 2.46-2.41 (m, 1H), 2.31-2.25 (m,1H), 2.08 (d, J = 11.8 Hz, 2H), 1.79 (br s, 2H), 1.55 (qd, J = 13.0, 3.3Hz, 2H), 1.32 (br s, 2H); MS: 652.0 (M − 1)⁻. 11/ 63

¹H-NMR (500 MHz, CD₃OD) δ: 8.28 (dd, J = 4.3, 9.3 Hz, 1H), 8.12 (d, J =7.5 Hz, 2H), 9.09 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 1.5, 8.0 Hz, 1H),7.77 (t, J = 7.8 Hz, 1H), 7.53- 7.33 (m, 6H), 7.04 (dd, J = 2.5, 9.0 Hz,1H), 3.48- 3.43 (m, 1H), 2.04 (br s, 2H), 1.80- 1.67 (m, 6H); MS: 672.0(M − 1)⁻. 11/ 64

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (d, J = 7.5 Hz, 2H), 8.16 (dd, J =4.3, 9.3 Hz, 1H), 7.84-7.81 (m, 2H), 7.71 (dd, J = 11.3, 1.3 Hz, 1H),7.62 (d, J = 7.0 Hz, 1H), 7.51-7.43 (m, 4H), 7.38 (d, J = 8.0 Hz, 1H),7.30 (dd, J = 2.5, 8.5 Hz, 1H), 3.56-3.51 (m, 1H), 2.30-2.22 (m, 1H),1.79-1.67 (m, 4H), 1.44 (q, J = 11.8 Hz, 2H), 1.22 (q, J = 11.8 Hz, 2H);MS: 688.0 (M − 1)⁻. 11/ 65

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.44 (dd, J = 4.3, 9.3 Hz, 1H), 8.07 (d, J= 7.0 Hz, 2H), 8.01 (d, J = 6.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H),7.56-7.32 (m, 8H), 7.19 (d, J = 11.0 Hz, 1H), 7.11 (s, 1H), 6.96 (dd, J= 2.5, 8.0 Hz, 1H), 6.70 (t, J = 55.8 Hz, 1H); MS: 697.9 (M − 1)⁻. 11/66

¹H-NMR (500 MHz, CD₃OD) δ: 8.29 (dd, J = 9.0, 4.0 Hz, 1H), 8.13-8.08 (m,3H), 7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.78-7.74 (m, 1H), 7.57-7.29 (m,6H), 7.03-6.99 (m, 1H), 3.18 (dd, J = 8.5, 6.0 Hz, 1H), 2.38-2.25 (m,2H), 1.85-1.05 (m, 8H); MS: 648.0 (M − 1)⁻. 11/ 67

¹H-NMR (500 MHz, CD₃OD) δ: 9.15 (br s, 2H), 8.48 (dd, J = 9.3, 4.3 Hz,1H), 8.08 (d, J = 1.0 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.55-7.48(m, 6H), 7.44-7.38 (m, 3H), 7.13 (dd, J = 8.0, 2.5 Hz, 1H), 7.01 (s,1H), 6.68 (t, J = 55.8 Hz, 1H); MS: 681.0 (M − 1)⁻. 11/ 68

¹H-NMR (400 MHz, CD₃OD) δ: 8.37 (dd, J = 9.2, 4.4 Hz, 1H), 8.10 (s, 1H),8.00 (d, J = 7.6 Hz, 1H), 7.55-7.41 (m, 8H), 7.27-7.22 (m, 1H), 7.16 (s,1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.70 (t,J = 55.4 Hz, 1H), 6.03 (d, J = 2.8 Hz, 1H), 3.72 (s, 3H); MS: 658.0 (M −1)⁻. 11/ 69

¹H-NMR (400 MHz, CD₃OD) δ: 8.38 (dd, J = 9.2, 4.4 Hz, 1H), 7.58 (d, J =8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.39-7.16 (m, 7H), 6.94-6.65 (m,3H), 2.38-2.34 (m, 1H), 1.61-1.55 (m, 1H), 1.50-1.45 (m, 1H), 1.10 (brs, 1H); MS: 628.0 and 630.0 (M − 1)⁻.

Example 12

Step 1: Methyl2-chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-5-methyl-[1,1′-biphenyl]-4-carboxylate(12a)

To a solution of compound 2a (200 mg, 0.33 mmol) in dioxane (2 mL) andwater (0.4 mL) was added methyl 4-bromo-5-chloro-2-methylbenzoate (105mg, 0.40 mmol), Cs₂CO₃ (215 mg, 0.66 mmol) and Pd(dppf)Cl₂ (20 mg). Themixture was stirred under N₂ at 100° C. for 8 h, cooled to rt, pouredinto EA (40 mL) and washed with H₂O (40 mL) and brine (40 mL). Theorganic layer was dried over Na₂SO₄, filtered, concentrated and purifiedby FCC (EA:PE=1:8) to give compound 12a as a white solid.

Step 2:2-Chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-5-methyl-[1,1′-biphenyl]-4-carboxylicacid (12)

To a solution of compound 12a (150 mg, 0.23 mmol) in HCl/dioxane (4N, 5mL) was added H₂O (0.5 mL) and the mixture was stirred at 90° C.overnight, concentrated, diluted with water and extracted with EA (3×).The combined organic layer was washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC to give compound 12 asa white solid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J=9.0, 4.5 Hz,1H), 8.03 (d, J=5.0 Hz, 1H), 7.82 (s, 1H), 7.54-7.46 (m, 3H), 7.40-7.32(m, 3H), 7.24 (d, J=8.0 Hz, 2H), 7.18 (dd, J=8.0, 3.0 Hz, 2H), 7.04-7.00(m, 2H), 2.53 (s, 3H), 2.21 (s, 3H); MS: 638.9 (M−1)⁻.

Example 12/1 to 12/10

The following Examples were prepared similar as described for Example 12using the appropriate building block.

# building block structure analytical data 12/1

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J= 5.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53-7.15 (m, 10H), 7.03 (d, J= 5.0 Hz, 1H), 6.98 (s, 1H), 2.55 (s, 3H), 2.23 (s, 3H); MS: 639.0 (M −1)⁻. 12/2

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 7.92 (d, J= 7.5 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7.53-7.46 (m, 3H), 7.30-7.26(m, 3H), 7.19-6.97 (m, 6H), 2.28 (s, 3H); MS: 643.0 (M − 1)⁻. 12/3

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 9.3, 4.3 Hz, 1H), 7.85-7.80 (m,2H), 7.53- 7.47 (m, 3H), 7.30-7.25 (m, 3H), 7.17 (d, J = 8.0 Hz, 3H),7.07 (dd, J = 7.8, 2.8 Hz, 1H), 7.04-6.96 (m, 2H), 2.27 (s, 3H); MS:642.9 (M − 1)⁻. 12/4

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J= 5.0 Hz, 1H), 7.59-7.50 (m, 3H), 7.43 (d, J = 7.5 Hz, 1H), 7.40-7.34(m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 8.5, 2.5 Hz, 1H), 7.10(s, 1H), 7.06 (d, J = 5.5 Hz, 1H), 6.94 (s, 1H), 3.82 (s, 3H), 2.22 (s,3H); MS: 655.0 (M − 1)⁻. 12/5

¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (dd, J = 9.3, 4.3 Hz, 1H), 7.84 (d, J =5.0 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.51-7.45 (m, 3H), 7.29-7.24 (m,3H), 7.16 (d, J = 8.0 Hz, 2H), 7.09-7.05 (m, 2H), 6.97-6.95 (m, 2H),3.95 (s, 3H), 2.27 (s, 3H); MS: 655.0 (M − 1)⁻. 12/6

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 7.98 (d, J= 5.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.48- 7.33 (m,4H), 7.29 (d, J = 8.3 Hz, 2H), 7.25- 7.13 (m, 2H), 6.99 (d, J = 5.0 Hz,1H), 6.93 (br s, 1H), 2.28 (s, 3H); MS: 581.0 (M − 1)⁻. 12/7

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 7.98 (d, J= 5.1 Hz, 1H), 7.61 (br s, 1H), 7.52 (br s, 1H), 7.48-7.28 (m, 7H),7.20-7.17 (m, 1H), 7.06 (d, J = 4.5 Hz, 1H), 6.64 (br s, 1H), 3.76 (brs, 3H), 2.28 (s, 3H); MS: 597.2 (M + H)⁺. 12/8

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (dd, J = 9.2, 4.4 Hz, 1H), 8.07 (d, J= 5.1 Hz, 1H), 7.59-7.49 (m, 2H), 7.45-7.31 (m, 4H), 7.28 (d, J = 8.3Hz, 2H), 7.20 (dd, J = 8.6, 2.6 Hz, 1H), 7.10-7.00 (m, 2H), 6.61 (s,1H), 4.25-4.22 (m, 1H), 2.26 (s, 3H), 1.30 (d, J = 6.5 Hz, 6H); MS:623.0 (M − 1)⁻. 12/9

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.31 (dd, J = 9.2, 4.4 Hz, 1H), 8.17 (d, J= 8.2 Hz, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.68(s, 1H), 7.55-7.44 (m, 2H), 7.40- 7.36 (m, 4H), 7.28-7.24 (m, 3H), 7.19(dd, J = 8.5, 2.5 Hz, 1H), 7.09 (d, J = 5.1 Hz, 1H), 2.22 (s, 3H); MS:631.0 (M − 1)⁻. 12/10

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.5, 4.5 Hz, 1H), 8.06 (br s,2H), 7.89 (d, J = 1.5 Hz, 1H), 7.80 (dd, J = 1.3, 7.8 Hz, 1H), 7.72 (t,J = 8.0 Hz, 1H), 7.55-7.48 (m, 7H), 7.36-7.31 (m, 2H), 7.02 (s, 1H),6.95 (dd, J = 2.3, 8.3 Hz, 1H), 6.68 (t, J = 55.8 Hz, 1H); MS: 715.9 (M− 1)⁻.

Example 13

3-(1-((4-Chlorophenyl)sulfonyl)-5-hydroxy-2-(thiophen-2-yl)-1t-indol-3-yl)thiophene-2-carbonitrile(13)

To a solution of compound 1/39 (775 mg, 1.52 mmol) in DCM (10 mL) wasadded BBr₃ (2 mL, 3N in DCM) at 0° C. and the mixture was stirred for 2h, poured into water (50 mL) and extracted with EA (3×20 mL). Thecombined organic layer was washed with aq. K₂CO₃ (30 mL) and brine (2×30mL), dried over Na₂SO₄, filtered, concentrated and purified by prep-HPLCto give compound 13 as a yellow solid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 9.63(s, 1H), 8.05-8.03 (m, 2H), 7.73 (d, J=5.0 Hz, 1H), 7.59 (d, J=8.5 Hz,2H), 7.47 (d, J=8.5 Hz, 2H), 7.19 (d, J=3.0 Hz, 1H), 7.12-7.10 (m, 1H),7.01-6.96 (m, 2H), 6.58 (s, 1H); MS: 496.9 (M+1)+.

Example 13/1

The following Example was prepared similar as described for Example 13using the appropriate starting material.

# starting material structure analytical data 13/1

¹H-NMR (500 MHz, DMSO-d₆) δ: 9.99 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H),7.70-7.68 (m, 2H), 7.63 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H),7.16-7.15 (m, 2H), 7.09- 7.08 (m, 1H), 7.00 (d, J = 5.0 Hz, 1H), 6.87(dd, J = 2.0, 8.5 Hz, 1H); MS: 496.7 (M + 1)⁺.

Example 14

Methyl2-((1-((4-chlorophenyl)sulfonyl)-3-(2-cyanothioahen-3-yl)-2-(thiophen-2-yl)-1H-indol-5-yl)oxy)acetate(14)

To a solution of compound 13 (120 mg, 0.25 mmol) in DMF (5 mL) was addedK₂CO₃ (69 mg, 0.50 mmol) and methyl 2-bromoacetate (46 mg, 0.30 mmol).The mixture was stirred at rt overnight, diluted with water andextracted with EA (3×20 mL). The combined organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered, concentrated and purified byFCC to give compound 14 as a brown solid.

Example 15

2-((1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indol-5-yl)oxy)aceticAcid (15)

To a solution of compound 14 (74 mg, 0.13 mmol) in MeOH (3 mL) was addedLIOH (1 mL, 2N) and the mixture was stirred at rt overnight, evaporated,adjusted to pH<2 with 2N HCl and extracted with EA (3×20 mL). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC to give compound 15 asa white solid. ¹H-NMR (500 MHz, DMSO-d) δ:13.02 (br s, 1H), 8.16 (d,J=9.0 Hz, 1H), 8.05 (d, J=5.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.60 (d,J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.21-7.11 (m, 3H), 7.03 (d, J=5.0Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 4.67 (s, 2H); MS: 554.6 (M+1)+.

Example 15/1 to 15/6

The following Examples were prepared similar as described for Example 14(optional) and Example 15 using the appropriate building blocks.

# building block(s) structure analytical data 15/ 1

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.12 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H),8.03 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 4.5 Hz, 1H), 7.59 (d, J = 9.0 Hz,2H), 7.48 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 2.5 Hz, 1H), 7.15-7.11 (m,2H), 7.02 (d, J = 5.0 Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 3.97 (t, J =6.5 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.93 (t, J = 6.8 Hz, 2H); MS:582.7 (M + 1)⁺. 15/ 2

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.03 (br s, 1H), 8.14 (d, J = 9.5 Hz, 1H),8.04 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 8.0 Hz,2H), 7.48 (d, J = 9.0 Hz, 2H), 7.21-7.20 (m, 1H), 7.15-7.11 (m, 2H),7.02 (d, J = 4.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 3.96 (t, J = 6.0 Hz,2H), 2.27 (t, J = 7.3 Hz, 2H), 1.75-1.62 (m, 4H); MS: 596.9 (M + 1)⁺.15/ 3

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.20 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H),7.72 (d, J = 5.0 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz,2H), 7.26 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 3.5 Hz, 1H), 7.12-7.10 (m,1H), 7.05 (dd, J = 2.0, 9.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 4.86 (s,2H); MS: 554.6 (M + 1)⁺. 15/ 4

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.02 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 2.0Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.54 (d, J= 8.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 3.0 Hz, 1H),7.11-7.00 (m, 3H), 4.13 (t, J = 6.5 Hz, 2H), 2.38 (t, J = 7.3 Hz, 2H),2.03- 1.97 (m, 2H); MS: 583.0 (M + 1)⁺. 15/ 5

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.03 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 1.5Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.54 (d, J= 8.5 Hz, 2H), 7.25 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.10(t, J = 4.3 Hz, 1H), 7.05-7.03 (m, 1H), 7.01 (d, J = 5.0 Hz, 1H), 4.12(t, J = 6.0 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H), 1.83-1.78 (m, 2H),1.73-1.68 (m, 2H); MS: 597.0 (M + 1)⁺. 15/ 6

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.20 (br s, 1H), 8.26 (d, J = 8.5 Hz, 1H),7.98 (d, J = 5.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.40-7.32 (m, 4H), 7.22 (d,J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H),6.93 (d, J = 5.0 Hz, 1H), 3.78 (s, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.59(t, J = 7.5 Hz, 2H); MS: 542.9 (M + 1)⁺.

Example 16

tert-Butyl3-(1-((4-chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-5-hydroxy-2-(thiophen-2-yl)-1H-indol-6-yl)propanoate(16)

To a solution of compound 13 (120 mg, 0.25 mmol) in DMF (3 mL) was addedK₂CO₃ (69 mg, 0.50 mmol) and methyl 2-bromoacetate (38 mg, 0.30 mmol).The mixture was stirred at rt overnight, diluted with water andextracted with EA (3×20 mL). The combined organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered, concentrated and purified byFCC to give compound 16 as a brown solid; MS: 624.7 (M+1)⁺.

Example 17

3-(1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-5-hydroxy-2-(thiophen-2-yl)-1H-indol-6-yl)propanoicAcid (17)

To a solution of compound 16 (32 mg, 50 μmol) in MeOH (2 mL) was addedNaOH (0.5 mL, 2N) and the mixture was stirred at rt overnight,concentrated, adjusted to pH<2 with 2N HCl and extracted with EA (3×20mL). The combined organic layer was washed with brine (20 mL), driedover Na₂SO₄, filtered, concentrated and purified by prep-HPLC to givecompound 17 as a white solid. ¹H-NMR (500 MHz, DMSO-d₆) δ:12.46 (s, 1H),10.42 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.77 (d, J=5.0 Hz, 1H), 7.70 (d,J=5.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.57 (d, J=9.0 Hz, 2H), 7.18 (d,J=3.0 Hz, 1H), 7.13-7.11 (m, 1H), 7.06 (d, J=5.0 Hz, 1H), 6.89 (d, J=9.0Hz, 1H), 4.43-4.37 (m, 2H), 2.61 (t, J=7.8 Hz, 2H); MS: 568.7 (M+1)⁺.

Example 18

Step 1: Methyl 3-amino-4-(thiophen-2-ylethynyl)benzoate (18a)

Methyl 3-amino-4-iodo-benzoate (1.0 g, 3.6 mmol) was dissolved indegassed THF (10 mL) and the mixture was degassed by bubbling a gentlestream of N₂ through the solution. After −5 min DIPEA (5.0 mL, 29 mmol)was added and the bubbling was continued for a few minutes beforeaddition of 2-ethynylthiophene (0.41 mL, 4.3 mmol). Then CuI (28 mg,0.15 mmol) was added directly followed by PdCl₂(PPh₃)₂ (49 mg, 70 μmol).The mixture was stirred at rt for 2.5 h, filtered through Celite andwashed with THF. EA (200 mL) was added and the mixture was washed withwater (50 mL) and brine (50 mL). The organic layer was dried overNa₂SO₄, filtered, concentrated and purified by FCC to give compound 18a.¹H-NMR (400 MHz, CDCl₃): 3.90 (s, 3H), 4.36 (br s, 2H), 7.02-7.04 (m,1H), 7.30-7.34 (m, 2H), 7.35-7.41 (m, 3H).

Step 2: Methyl4-(thiophen-2-ylethynyl)-3-(2.2.2-trifluoroacetamido)benzoate (18b)

Compound 18a (450 mg, 1.68 mmol) was dissolved in dry THF (1 mL) and themixture was cooled to 0° C. Then 2,2,2-trifluoroacetic anhydride (0.47mL, 3.4 mmol) was added dropwise and the mixture was stirred for 15 min,diluted with EA (100 mL) and washed with NaHCO₃-water (1:1, 50 mL) andbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered,concentrated and purified by FCC to give the compound 18b as a yellowsolid. ¹H-NMR (400 MHz, CDCl₃): 3.95 (s, 3H), 7.08-7.10 (m, 1H),7.37-7.38 (m, 1H), 7.43-7.44 (m, 1H), 7.60-7.63 (m, 1H), 7.90-7.92 (m,1H), 8.75 (br s, 1H), 8.97 (d, 1H).

Step 3: Methyl3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6-carboxylate (18c)

A dried microwave-tube was charged with compound 18b (187 mg, 0.53mmol), Cs₂CO₃ (259 mg, 0.79 mmol), Pd(PPh₃)₄ (31 mg, 0.03 mmol) and3-bromothiophene-2-carbonitrile (149 mg, 0.79 mmol). Degassed CH₃CN (2.5mL) was added and the tube was purged with N₂. The mixture was stirredat 100° C. for 1 h, cooled, diluted with EA (80 mL) and washed withNaHCO₃:water (1:1, 40 mL), water (20 mL) and brine (15 mL). The organiclayer was dried (Na₂SO₄), filtered and concentrated to give compound 18cas a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): 3.88 (s, 3H), 7.17-7.19(m, 1H), 7.33-7.46 (m, 3H), 7.64-7.71 (m, 2H), 8.10 (s, 1H), 8.19-8.21(m, 1H), 12.32 (s, 1H).

Step 4: Methyl1-((4-chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6-carboxylate(18)

Compound 18c (180 mg, 0.49 mmol) was dissolved in THF (15 mL) and NaH(3.9 mmol dispersed in mineral oil) was added followed by4-chlorobenzenesulfonyl chloride (188 mg, 0.89 mmol). The mixture wasstirred at rt for 1 h, quenched by careful addition of water, dilutedwith EA (250 mL) and washed with water (100 mL) and brine (100 mL). Theorganic layer was dried over Na₂SO₄, filtered, concentrated and purifiedby FCC and then prep-HPLC (55-60% acetonitrile in 15 mM NH₄HCO₃ buffer,pH 10) to give compound 18 as a white solid.

Example 19

1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6-carboxylicAcid (19)

Compound 18 (77 mg, 0.14 mmol) was dissolved in THF (4 mL) and cooled to0° C. In a separate 4 mL vial LiOH (48 mg, 2.0 mmol) was dissolved inwater (4 mL) and cooled to 0° C. The base solution was added dropwise tothe solution of compound 18 and the resulting mixture was stirredvigorously overnight (the reaction slowly adapted rt). The reaction wasre-cooled to 0° C., quenched with 2N HCl (1.4 mL) and extracted with EA(3×20 mL). The combined organic layer was dried over MgSO₄, filtered,concentrated and purified by prep-HPLC (Xbridge, 30-60% acetonitrile in0.1% TFA buffer) to give compound 19 as a white solid. ¹H-NMR (400 MHz,DMSO-d₆): 7.07 (d, 1H), 7.12-7.15 (dd, 1H), 7.24-7.25 (dd, 1H),7.40-7.50 (m 3H), 7.55-7.63 (m 2H), 7.76-7.77 (dd, 1H), 7.97-8.00 (dd,1H), 8.06 (d, 1H), 8.89 (m, 1H), 13.29 (br s, 1H); MS: 542 (M+NH₃+1)⁺.

Example 20

Step 1: 2-(Thiophen-2-ylethynyl)aniline (20a)

To a mixture of 2-iodoaniline (40.0 g, 183 mmol), CuI (700 mg, 3.70mmol), Pd(PPh₃)₂Cl₂ (1.30 g, 1.83 mmol) and TEA (120 mL) in ACN (1 L)was added 2-ethynylthiophene (24.0 g, 219 mmol) under N₂ via a syringe.The mixture was stirred at 50° C. overnight, cooled, filtered,concentrated and purified by FCC (PE:EA=50:1) to afford compound 20a asa yellow solid.

Step 2: 4-Chloro-N-(2-(thiophen-2-ylethynyl)phenyl)benzenesulfonamide(20b)

To a solution of compound 20a (10.0 g, 50.3 mmol),4-chlorobenzenesulfonyl chloride (13.1 g, 62.3 mmol) and pyridine (4.17g, 52.8 mmol) in DCM (150 mL) was added DMAP (306 mg, 2.5 mmol) at rt.The mixture was heated to reflux overnight, cooled, washed with 2N HCland extracted with DCM. The organic layer was dried over Na₂SO₄,filtered, concentrated and then the residue was washed with PE to givecompound 20b as a yellow solid.

Step 3:1-((4-Chlorophenyl)sulfonyl)-3-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(thiophen-2-yl)-1H-indole(20c)

A mixture of compound 20b (11.0 g, 29.4 mmol), Cs₂CO₃ (19 g, 59 mmol),AsPh₃ (1.36 g, 4.40 mmol), Pd₂(dba)₃ (1.34 g, 1.48 mmol) and B₂Pin₂ (15g, 59 mmol) in dioxane (175 mL) was stirred under N₂ at 60° C. for 2 h,cooled, filtered, concentrated and purified by FCC (PE:EA=20:1 to 5:1)to afford compound 20c as a white solid.

Step 4:1-((4-Chlorophenyl)sulfonyl)-3-(2-chlorothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole(20)

A solution of compound 20c (200 mg, 0.40 mmol),3-bromo-2-chlorothiophene (79 mg, 0.40 mmol), Pd(PPh₃)₄(46 mg, 40 μmol)and K₃PO₄ (404 mg, 1.6 mmol) in dioxane/H₂O (10:1, 22 mL) was stirredunder N₂ at 100° C. overnight, cooled, filtered and washed with DCM.Then the filtrate was concentrated and purified by prep-HPLC to affordcompound 20 as a white solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 8.35 (d, J=6.6Hz, 1H), 7.40-7.25 (m, 8H), 7.13 (d, J=0.6 Hz, 1H), 7.05-7.03 (m, 2H),6.61 (d, J=4.2 Hz, 1H); MS: 589.0 (M+1)+.

Example 20/1 to 20/25

The following Examples were prepared similar as described for Example 20using the appropriate building blocks.

# building block(s) structure analytical data 20/ 1

¹H-NMR (CDCl₃, 300 MHz) δ: 1.02 (s, 9H), 6.67 (s, 1H), 6.98-7.01 (m,1H), 7.08 (s, 1H), 7.19 (s, 1H), 7.28- 7.30 (m, 3H), 7.35-7.43 (m, 3H),7.47-7.50 (m, 2H), 8.32 (s, 1H). 20/ 2

¹H-NMR (CDCl₃, 300 MHz) δ: 7.04- 7.01 (m, 1H), 7.42-7.19 (m, 8H),7.48-7.57 (m, 2H), 8.41 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 8.70 (d, J =4.5 Hz, 1H); MS: 476.0 (M + 1)⁺. 20/ 3

¹H-NMR (CDCl₃, 300 MHz) δ: 6.29 (t, J = 54.9 Hz, 1H), 6.72-6.73 (m, 1H),7.03 (dd, J = 3.8, 5.0 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 7.25-7.46 (m,9H), 8.37 (d, J = 8.4 Hz, 1H); MS: 505.9 (M + 1)⁺. 20/ 4

¹H-NMR (CDCl₃, 300 MHz) δ: 7.04 (dd, J = 3.8, 5.3 Hz, 1H), 7.15 (d, J =3.3 Hz, 1H), 7.20 (dd, J = 0.9, 3.6 Hz, 1H), 7.26-7.47 (m, 8H), 7.94 (d,J = 3.3 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H); MS: 498.0 (M + 18)⁺. 20/ 5

¹H-NMR (CDCl₃, 300 MHz) δ: 2.54 (s, 3H), 6.97 (dd, J = 3.8, 8.6 Hz, 1H),7.02 (s, 1H), 7.07-7.10 (m, 1H), 7.23-7.57 (m, 10H), 8.14-8.17 (m, 1H),8.32 (d, J = 8.4 Hz, 1H); MS: 545.0 (M + 18)⁺. 20/ 6

¹H-NMR (CDCl₃, 300 MHz) δ: 6.99- 7.02 (m, 1H), 7.16-7.42 (m, 11H), 7.47(t, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H); MS: 493.0 (M + 1)⁺. 20/ 7

¹H-NMR (CDCl₃, 300 MHz) δ: 7.09 (dd, J = 3.9, 5.1 Hz, 1H), 7.26-7.28 (m,2H), 7.36-7.41 (m, 6H), 7.48- 7.52 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H),8.60 (d, J = 2.4 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H); MS: 477.0 (M + 1)⁺.20/ 8

20/ 9

20/ 10

20/ 11

¹H-NMR (CDCl₃, 300 MHz) δ: 6.80 (d, J = 5.1 Hz, 1H), 6.98-7.08 (m, 3H),7.20-7.22 (m, 1H), 7.33-7.53 (m, 7H), 8.39 (d, J = 8.4 Hz, 1H); MS 482.0(M + 18)⁺. 20/ 12

¹H-NMR (CDCl₃, 300 MHz) δ: 6.74- 6.84 (m, 2H), 6.89 (d, J = 5.1 Hz, 1H),7.00-7.03 (m, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.32-7.51 (m, 6H), 8.30 (d,J = 9.0 Hz, 1H); MS: 483.0 (M + 1)⁺. 20/ 13

¹H NMR (CDCl₃, 300 MHz) δ: 6.81 (d, J = 4.8 Hz, 1H), 7.06 (dd, J = 3.2,5.0 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.29-7.49 (m, 9H), 8.38 (d, J =8.7 Hz, 1H). 20/ 14

¹H-NMR (CDCl₃, 300 MHz) δ: 3.79 (s, 3H), 6.77-6.79 (m, 3H), 7.05 (dd, J= 3.8, 5.0 Hz, 1H), 7.19 (dd, J = 0.9, 3.6 Hz, 1H), 7.31-7.49 (m, 7H),8.41 (d, J = 8.4 Hz, 1H); MS: 477.0 (M + 1)⁺. 20/ 15

¹H-NMR (CDCl₃, 300 MHz) δ: 2.55- 2.60 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H),3.63 (s, 3H), 6.79 (d, J = 5.1 Hz, 1H), 7.04 (dd, J = 3.9, 5.1 Hz, 1H),7.15-7.18 (m, 3H), 7.33-7.50 (m, 7H), 8.40 (d, J = 8.4 Hz, 1H); MS:550.0 (M + 18)⁺. 20/ 16

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.17 (d, J = 8.4 Hz, 1H), 7.48-7.33 (m,10H), 6.98-6.94 (m, 2H), 3.75 (s, 3H), 2.29-2.08 (m, 3H), 1.77- 1.36 (m,5H); MS: 486.2 (M + 18)⁺. 20/ 17

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.61 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H),8.12 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96-7.92 (m, 1H),7.83-7.79 (m, 1H), 7.55-7.48 (m, 3H), 7.37-7.29 (m, 7H), 7.05- 7.03 (m,2H), 3.79 (s, 3H); MS: 516.1 (M + 1)⁺. 20/ 18

¹H-NMR (DMSO-d₆, 300 MHz) δ: 8.31 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4Hz, 1H), 7.61-7.50 (m, 2H), 7.43-7.01 (m, 13H), 3.79 (s, 3H); MS 538.1(M + 18)⁺. 20/ 19

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.23 (d, J = 8.4 Hz, 1H), 7.51-7.21 (m,14H), 7.00 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.86-2.80 (m, 1H),2.60-2.49 (m, 2H), 2.15-2.09 (m, 1H); MS: 534.1 (M + 18)⁺. 20/ 20

¹H-NMR (DMSO-d₆, 400 MHz) δ: 9.07 (dd, J = 1.2, 4.0 Hz, 1H), 8.44 (d, J= 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.79(dd, J = 4.2, 8.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 3H),7.36-7.27 (m, 7H), 7.03 (d, J = 9.2 Hz, 2H), 3.79 (s, 3H); MS: 516.1(M + 1)⁺. 20/ 21

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.21 (d, J = 8.4 Hz, 1H), 7.47-7.25 (m,10H), 7.14 (d, J = 8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.65 (d, J = 4.8 Hz,1H), 3.76 (s, 3H), 1.85 (s, 3H); MS: 460.1 (M + 1)⁺. 20/ 22

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.20 (d, J = 8.4 Hz, 1H), 7.44-7.29 (m,10H), 7.02-6.98 (m, 2H), 6.75 (d, J = 6.0 Hz, 1H), 6.41 (d, J = 5.6 Hz,1H), 3.77 (s, 3H), 3.54 (s, 3H); MS: 476.1 (M + 1)⁺. 20/ 23

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.26 (d, J = 8.0 Hz, 1H), 7.52-7.28 (m,10H), 7.01 (d, J = 9.2 Hz, 2H), 6.77 (s, 1H), 3.77 (s, 3H), 2.43 (s,3H); MS: 502.1 (M + 18)⁺. 20/ 24

20/ 25

Example 21

3-(1-((4-Chlorophenyl)sulfonyl)-2-(thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carboxylicAcid (21)

A solution of compound 20/1 (95 mg, 0.24 mmol) and TFA (0.5 mL) in DCM(2.5 mL) was stirred at rt for 4 h, concentrated and then the residuewas triturated with PE including a little amount of EA to give compound21 as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ:6.79 (d, J=3.9 Hz, 1H),7.02-7.04 (m, 1H), 7.11 (dd, J=1.1, 2.6 Hz, 1H), 7.21 (d, J=5.7 Hz, 1H),7.26-7.40 (m, 6H), 7.45-7.49 (m, 1H), 7.55 (d, J=3.9 Hz, 1H), 8.35 (d,J=6.3 Hz, 1H); MS: 497.9 (M−1)⁻.

Example 21/1 to 21/3

The following Examples were prepared similar as described for Example 20using the appropriate starting material.

# starting material structure analytical data 21/ 1

¹H-NMR (CDCl₃, 400 MHz) δ: 8.34 (d, J = 6.3 Hz, 1H), 7.58-7.13 (m, 10H),6.97-6.87 (m, 2H), 6.66 (s, 1H), 4.49 (br s, 2H); MS: 547.0 (M − 1)⁻.21/ 2

¹H-NMR (DMSO-d₆, 300 MHz) δ: 8.21 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 4.8Hz, 1H), 7.58-7.48 (m, 6H), 7.37-7.32 (m, 1H), 7.16-7.04 (m, 4H), 6.87(d, J = 7.8 Hz, 1H), 4.83 (s, 2H); MS: 546.9 (M − 1)⁻. 21/ 3

¹H-NMR (CD₃OD, 400 MHz) δ: 8.43 (dd, J = 9.4, 4.2 Hz, 1H), 8.05 (d, J =8.0 Hz, 2H), 7.98 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0, 2.0 Hz, 1H),7.71 (t, J = 8.0 Hz, 1H), 7.54-7.30 (m, 9H), 7.09 (s, 1H), 6.94 (dd, J =8.4, 2.8 Hz, 1H), 6.67 (t, J = 55.6 Hz, 1H), 4.12 (s, 2H); MS: 737.0 (M− 1)⁻.

Example 22

3-(1-((4-Chlorophenylsulfonyl)-2-(thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carboxamide(22)

To a solution of compound 21 (90 mg, 0.18 mmol) and HATU (137 mg, 0.36mmol) in DMF (5 mL) was added DIEA (116 mg, 0.90 mmol) at rt. Thesolution was stirred for 20 min, then NH₄Cl (19 mg, 0.36 mmol) was addedand the mixture was stirred at rt for 2 h, cooled, diluted with waterand stirred for 10 min. The mixture was filtered to give compound 22 asa yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 5.16 (br s, 2H), 6.68 (d,J=5.1 Hz, 1H), 7.03 (dd, J=3.6, 5.1 Hz, 1H), 7.14 (dd, J=1.2, 3.6 Hz,1H), 7.23-7.49 (m. 9H), 8.39 (d, J=8.4 Hz, 1H); MS: 499.0 (M+1).

Example 23

1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-5-carboxylicAcid (23)

A solution of compound 20/10 (49 mg, 90 μmol) and LiOH.H₂O (12 mg, 0.27mmol) in THF/H₂O (3:1, 8 mL) was stirred at rt overnight, concentrated,adjusted to pH to 5-6 with 1N HCl and purified by prep-HPLC to givecompound 23 as a yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 8.48 (d, J=8.7Hz, 1H), 8.22-8.18 (m, 2H), 7.53 (d, J=5.1 Hz, 1H), 7.44-7.26 (m, 6H),7.10-7.07 (m, 1H), 6.88 (d, J=4.8 Hz, 1H); MS: 522.8 (M−1)⁻.

Example 23/1 to 23/3

The following Example was prepared similar as described for Example 23using the appropriate starting material.

# starting material structure analytical data 23/ 1

¹H-NMR (CDCl₃, 400 MHz) δ: 8.37 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 5.1,1H), 7.52-7.45 (m, 2H), 7.39-7.25 (m, 6H), 7.15 (d, J = 3.6 Hz, 1H),7.07-7.04 (m, 1H), 6.91 (d, J = 5.4 Hz, 1H), 2.92- 2.86 (m, 2H), 2.56(t, J = 7.4 Hz, 2H); MS: 519.0 (M + 1)⁺, 536.1 (M + 18)⁺. 23/ 2

23/ 3

Example 24

Step 1: Meth 3-(2-iodophenyl)amino)propanoate (24a)

A mixture of 2-iodoaniline (50 g, 288 mmol) and methyl acrylate (103 mL,1.14 mol) in AcOH (60 mL) was stirred at 90° C. in a sealed tube for 48h, cooled and filtered. The filtrate was concentrated, diluted with aq.Na₂CO₃ and extracted with EA (2×100 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated to afford compound24a as a yellow oil.

Step 2: Methyl 3-((2-iodophenyl)(methyl)amino)propanoate (24b)

A mixture of compound 24a (17.7 g, 58.1 mmol), CH₃ (29 mL, 46 mmol) andK₂CO₃ (16.3 g, 118 mmol) in ACN (120 mL) was stirred at 80° C. in asealed tube for 48 h, cooled and filtered. The filtrate wasconcentrated, diluted with H₂O and extracted with EA (2×100 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to afford crude compound 24b as a yellow oil.

Step 3: Methyl 3-(methyl(2-(thiophen-2-ylethynyl)phenyl)amino)propanoate(24c)

A mixture of compound 24b (24.8 g, 77.7 mmol), 2-ethynyl-thiophene (15.6mL, 154 mmol), CuI (296 mg, 1.56 mmol), Pd(PPh₃)₂Cl₂ (546 mg, 0.778mmol) and TEA (39.3 g, 389 mmol) in ACN (90 mL) was stirred at 80° C. ina sealed tube overnight, cooled and filtered. The filtrate wasconcentrated and purified by FCC (PE:EA=20:1) to afford compound 24c asa brown oil.

Step 4: Methyl3-(3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indol-1-yl)propanoate(24d)

A mixture of compound 24c (23.2 g, 77.6 mmol),3-bromo-thiophene-2-carbonitrile (16.1 g, 85.6 mmol), n-Bu₄NI (2.90 g,7.76 mmol) and PdCl₂(dppf) (1.70 g, 2.33 mmol) in ACN (150 mL) wasstirred at 90° C. under N₂ overnight, cooled, quenched with H₂O andextracted with EA (2×150 mL). The combined organic layer was washed withbrine, dried over Na₂SO₄, concentrated and purified by FCC (PE:EA=5:1)to afford compound 24d as a brown oil; MS: 393.0 (M+1)⁺.

Step 5: 3-(2-(Thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carbonitrile(24e)

A mixture of compound 24d (12.6 g, 32.1 mmol) and DBU (10.1 mL, 64.2mmol) in DMF (100 mL) was stirred at 120° C. overnight, cooled, dilutedwith H₂O and extracted with EA (2×100 mL). The combined organic layerwas washed with H₂O (2×100 mL) and brine, dried over Na₂SO₄,concentrated and purified by FCC (PE:EA=5:1) to afford compound 24e as ayellow solid; MS: 307.0 (M+1)⁺.

Step 6:3-(1-(Cyclohexylsulfonyl)-2-(thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carbonitrile(24)

To a solution of compound 24e (200 mg, 0.65 mmol) in THF (20 mL) at −78°C. under N₂ was added LiHMDS (1.0 M in THF, 0.8 mL, 0.8 mmol) dropwise.The mixture was stirred at −78° C. for 30 min, then cyclohexanesulfonylchloride (144 mg, 0.80 mmol) was added. The mixture was stirred at −78°C. for 2 h, diluted with aq. NH₄Cl and extracted with DCM (3×). Thecombined organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by prep-HPLC to afford compound 24 as a yellow solid. ¹H-NMR(CDCl₃, 300 MHz) δ: 1.08-1.12 (m, 3H), 1.46-1.60 (m, 3H), 1.73-1.77 (m,4H), 3.06-3.16 (m, 1H), 6.86 (d, J=5.4 Hz, 1H), 7.05 (dd, J=3.6, 4.8 Hz,1H), 7.27-7.51 (m, 6H), 8.19 (d, J=8.4 Hz, 1H); MS: 467.7 (M+Na)⁴.

Example 25

Step 1: tert-Butyl 2-(thiazol-5-yl)-1H-indole-1-carboxylate (25a)

A mixture of tert-butyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(4.20 g, 12.2 mmol), 5-bromo-thiazole (2.00 g, 12.2 mmol), Pd(dppf)Cl₂(877 mg, 1.20 mmol) and K₂CO₃ (5.10 g, 36.6 mmol) in dioxane/H₂O (50mL/5 mL) was stirred at 100° C. under N₂ overnight, cooled, diluted withEA (300 mL) and washed with brine. The organic layer was dried overNa₂SO₄, filtered, concentrated and purified by FCC (PE:EA=5:1) to givecompound 25a as a colorless oil.

Step 2: tert-Butyl 3-bromo-2-(thiazol-5-yl)-1H-indole-1-carboxylate(25b)

A mixture of compound 25a (2.6 g, 8.7 mmol) and NBS (1.85 g, 10.4 mmol)in DMF (50 mL) was stirred at rt under N₂ overnight, diluted with waterand extracted with EA (3×50 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered, concentrated and purified byFCC (PE:EA=10:1) to give compound 25b as a yellow solid.

Step 3: tert-Butyl3-(2-cyanothiophen-3-yl)-2-(thiazol-5-yl)-1H-indole-1-carboxylate (25c)

A mixture of compound 25b (620 mg, 1.60 mmol),3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carbonitrile(376 mg, 1.60 mmol), Pd(dppf)Cl₂ (117 mg, 160 μmol) and K₂CO₃ (662 mg,4.80 mmol) in dioxane/H₂O (20 mL/2 mL) was stirred at 100° C. under N₂overnight, cooled, diluted with EA (200 mL) and washed with brine. Theorganic layer was dried over Na₂SO₄, filtered, concentrated and purifiedby FCC (PE:EA=5:1) to give compound 25c as a yellow oil.

Step 4: 3-(2-(Thiazol-5-yl)-1H-indol-3-yl)thiophene-2-carbonitrile (25d)

A mixture of compound 25c (320 mg, 0.79 mmol) and TFA (4 mL) in DCM (10mL) was stirred at rt overnight, concentrated, neutralized with sat. aq.NaHCO₃ and extracted with EA (3×30 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated toafford compound 25d, which was used in the next step without furtherpurification.

Step 5:3-(1-((4-Chlorophenyl)sulfonyl-2-(thiazol-5-yl)-1H-indol-3-yl)thiophene-2-carbonitrile(25)

To a solution of compound 25d (200 mg, 0.65 mmol) in THF (10 mL) wasadded NaH (39 mg, 0.98 mmol) under N₂ at 0° C. The mixture was stirredat 0° C. for 30 min, then 4-chloro-benzene-sulfonyl chloride (165 mg,0.78 mmol) was added. The mixture was stirred at 0° C. for 30 min,poured into sat. aq. NH₄Cl (50 mL) and extracted with EA (3×50 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by prep-HPLC (CH₃CN/H₂O=20% to 95%,5 mmol NH₄HCO₃) to afford compound 25 as a yellow solid. ¹H-NMR(DMSO-d₆, 400 MHz) δ: 9.28 (d, J=0.8 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H),8.08 (d, J=5.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.66-7.56 (m, 5H),7.43-7.39 (m, 2H), 7.11 (d, J=5.2 Hz, 1H); MS: 481.8 (M+1)⁺.

Example 26

Step 1: tert-Butyl 3-(2-cyanothiophen-3-yl)-1H-indole-1-carboxylate(26a)

To a solution of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(2.0 g, 5.8 mmol), 3-bromo-thiophene-2-carbonitrile (1.1 g, 5.8 mmol)and K₂CO₃ (2.40 g, 17.4 mmol) in dioxane/H₂O (20 mL/2 mL) was addedPd(dppf)Cl₂ (413 mg, 0.58 mmol) under N₂. The mixture was stirred at 90°C. for 4 h, evaporated and purified by FCC (PE:EA=20:1 to 10:1) toafford compound 26a as a yellow oil.

Step 2: tert-Butyl2-bromo-3-(2-cyanothiophen-3-yl)-1H-indole-1-carboxylate (26b)

To a solution compound 26a (1.30 g, 4.01 mmol) in CCl₄ (20 mL) wereadded NBS (1.40 g, 8.02 mmol) and AIBN (65.4 mg, 401 μmol). The mixturewas stirred at 100° C. for 48 h, evaporated and purified by FCC(PE:EA=10:1) to afford compound 26b as a yellow oil.

Step 3: tert-Butyl3-(2-cyanothiophen-3-yl)-2-phenyl-1H-indole-1-carboxylate (26c)

To a solution of compound 26b (500 mg, 1.24 mmol), PhB(OH)₂ (302 mg,2.48 mmol) and K₂CO₃ (513 mg, 3.72 mmol) in dioxane (15 mL) was addedPd(dppf)Cl₂ (88.4 mg, 124 μmol) under N₂. The mixture was stirred at 90°C. overnight, concentrated and purified by FCC (PE:EA=10:1) to affordcompound 26c as a yellow oil.

Step 4: 3-(2-Phenyl-1H-indol-3-yl)thiophene-2-carbonitrile (26d)

To a solution of compound 26c (616 mg, 1.54 mmol) in DCM (4 mL) wasadded TFA (2 mL). The mixture was stirred at rt for 2 h, concentratedand purified to afford compound 26d as a white solid.

Step 5:3-(1-((4-Chlorophenyl)sulfonyl)-2-phenyl-1H-indol-3-yl)thiophene-2-carbonitrile(26)

To a solution of compound 26d (147 mg, 488 μmol) in DMF (5 mL) was addedNaH (78 mg, 2.0 mmol) under N₂ at 0° C. The mixture was stirred at 0° C.for 30 min, then 4-chloro-benzenesulfonyl chloride (310 mg, 1.46 mmol)was added. The mixture was stirred at 0° C. for 30 min, quenched withsat. aq. NH₄Cl and extracted with DCM (3×20 mL). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered, concentratedand purified by FCC (PE:EA=20:1) to afford compound 26 as a white solid.¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.25 (d, J=8.0 Hz, 1H), 7.99 (d, J=5.2 Hz,1H), 7.59 (dd, J=2.0, 6.8 Hz, 2H), 7.53-7.27 (m, 10H), 6.96 (d, J=4.8Hz, 1H); MS: 491.7 (M+18)⁺.

Example 26/1

The following Example was prepared similar as described for Example 26using the appropriate starting material.

# starting material structure analytical data 26/1

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.25 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 5.6Hz, 1H), 7.61- 7.58 (m, 2H), 7.55-7.48 (m, 3H), 7.43-7.32 (m, 4H),7.25-7.21 (m, 2H), 7.00 (d, J = 4.8 Hz, 1H); MS: 509.6 (M + 18)⁺.

Example 27

2-(4-((3-(2-Cyanothiophen-3-yl)-2-phenyl-1-H-indol-1-yl)sulfonyl)phenoxy)aceticAcid (27)

To a solution of compound 1/43 (70 mg, 130 μmol) in MeOH (5 mL) wasadded NaOH (2N, 0.5 mL) and the mixture was stirred overnight. Then theMeOH was removed and the solution was adjusted to pH<2 with 2N HCl,extracted with EA (10 mL) and washed with brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered, concentrated and purified byprep-HPLC to afford compound 27 as a white solid. ¹H-NMR (500 MHz,DMSO-d₆) δ:13.21 (br s, 1H), 8.26 (d, J=8.5 Hz, 1H), 7.99 (d, J=5.0 Hz,1H), 7.52-7.34 (m, 8H), 7.27 (d, J=7.0 Hz, 2H), 7.01-6.99 (m, 3H), 4.75(s, 2H); MS: 515.1 (M+1)⁺.

Example 27/1 to 27/3

The following Examples were prepared similar as described for Example 27using the appropriate starting material.

# starting material structure analytical data 27/ 1

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.55 (br s, 1H), 8.26 (d, J = 9.0 Hz, 1H),8.00 (d, J = 5.0 Hz, 1H), 7.55-7.34 (m, 10H), 7.28 (d, J = 7.0 Hz, 2H),6.98 (d, J = 5.0 Hz, 1H), 3.61 (s, 2H); MS: 499.1 (M + 1)⁺. 27/ 2

1H-NMR (500 MHz, DMSO-d6) δ: 13.18 (br s, 1H), 8.32 (d, J = 8.5 Hz, 1H),8.17 (s, 1H), 8.00 (d, J = 5.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.86(d, J = 8.5 Hz, 2H), 7.63-7.52 (m, 4H), 7.45-7.32 (m, 7H), 6.97 (d, J =5.0 Hz, 1H); MS: 561.2 (M + 1)⁺. 27/ 3

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.85 (br s, 1H), 8.21 (d, J = 8.0 Hz, 1H),8.01 (d, J = 5.5 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.32 (m, 8H), 7.00 (d,J = 5.0 Hz, 1H), 6.95 (d, J = 3.5 Hz, 1H), 3.91 (s, 2H); MS: 505.0 (M +1)⁺.

Example 28

3-(4-(3-(2-Cyanothiophen-3-yl)-1-((4-methoxyphenyl)sulfonyl)-1H-indol-2-yl)phenyl)propan-amide(28)

To a solution of compound 15/6 (200 mg, 0.40 mmol) in DMF (10 mL) wasadded EDCl (100 mg, 0.50 mmol), DMAP (60 mg, 0.50 mmol) and NH₄Cl (70mg, 0.50 mmol) and the mixture was stirred at rt for 12 h, diluted withwater (100 mL) and extracted with EA (3×100 mL). The combined organiclayer was washed with brine (50 mL), dried over Na₂SO₄, filtered,concentrated and purified by prep-HPLC to give compound 28 as a whitesolid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=8.0 Hz, 1H), 7.98 (d,J=5.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.40-7.33 (m, 5H), 7.20 (d, J=8.0 Hz,2H), 7.15 (d, J=8.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.93 (d, J=5.0 Hz,1H), 6.84 (s, 1H), 3.78 (s, 3H), 2.85 (t, J=8.0 Hz, 2H), 2.41 (t, J=8.0Hz, 2H); MS: 542.1 (M+1)⁺.

Example 29

Step 1: Methyl2-chloro-3′-((2-((4-(difluoromethyl)phenyl)sulfonamido)-5-fluorophenyl)ethynyl)-[1,1′-biphenyl]-4-carboxylate(29a)

Compound 29a was synthesized similar as described in Example 1, Step 1and 2 using the appropriate building blocks.

Step 2: Methyl2-chloro-3′-(1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(29b)

To a solution of compound 29a (400 mg, 0.70 mmol) in MeCN (12.0 mL) wasadded K₂CO₃ (193 mg, 1.40 mmol) and Pd(PPh₃)₄ (81 mg, 70 μmol) under N₂.The mixture was stirred at 100° C. for 2 h, cooled to rt, poured into EA(200 mL) and washed with H₂O (2×20 mL) and brine (20 mL). The organiclayer was dried over Na₂SO₄, concentrated and purified by FCC(EA:PE=1:4) to give compound 29b as a colorless oil.

Step 3: Methyl3′-(3-bromo-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-2-chloro-[1,1′-biphenyl]-4-carboxylate(29c)

To a solution of compound 29b (150 mg, 0.26 mmol) in THE (15 mL) wasadded NBS (56 mg, 0.31 mmol). The mixture was stirred at rt overnight,poured into EA (200 mL) and washed with H₂O (2×20 mL) and brine (20 mL).The organic layer was dried over Na₂SO₄, concentrated and purified byprep-TLC (EA:PE=1:4) to give compound 29c as a white solid.

Step 4: Methyl2-chloro-3′-(1-((4-(difluoromethyl)phenyl)sulfonyl)-3-(2,6-dimethylphenyl)-5-fluoro-1H-indol-2-yl)-(1,1′-biphenyl)-4-carboxylate(29)

To a solution of compound 29c (150 mg, 0.23 mmol) in dioxane (8 mL) wasadded 2,6-dimethyl-phenylboronic Acid (45 mg, 0.30 mmol), Cs₂CO₃ (176mg, 0.46 mmol) and Pd(dppf)Cl₂ (17 mg, 23 μmol) under N₂. The mixturewas stirred at 90° C. overnight, cooled to rt, poured into EA (200 mL)and washed with H₂O (2×20 mL) and brine (20 mL). The organic layer wasdried over Na₂SO₄, concentrated and purified by prep-TLC (EA:PE=1:4) togive compound 29 as a colorless oil.

Example 29/1 to 29/3

The following Examples were prepared similar as described for Example 29using the appropriate starting material(s).

# starting material(s) structure 29/1

29/2

29/3

Example 30

rac-(1R,2R)-2-(3-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1l-indol-2-yl)phenyl)cyclopropane-1-carboxylicAcid (30)

To a solution of compound 1/56 (130 mg, 0.23 mmol) in MeOH (10 mL) wasadded LiOH—H₂O (49 mg, 1.18 mmol) and the mixture was stirred at rt for1 h. Then the mixture was concentrated, adjusted to pH<4 with 2N aq. HCland extracted with EA (3×30 mL). The combined organic layer was washedwith brine (10 mL), dried over Na₂SO₄, concentrated and purified byprep-HPLC to give compound 30 as a white solid. ¹H-NMR (500 MHz,DMSO-d₆) δ: 12.36 (s, 1H), 8.27 (d, J=10.0 Hz, 2H), 8.01 (d, J=5.5 Hz,1H), 7.52-7.48 (m, 1H), 7.41-7.26 (m, 8H), 7.10-7.08 (m, 1H), 7.02-6.98(m, 1H), 6.88 (s, 1H), 2.38-2.33 (m, 1H), 2.31 (s, 3H), 1.73-1.68 (m,1H), 1.44-1.39 (m, 1H), 1.25-1.18 (m. 1H). MS: 521 (M−18+H)⁺.

Example 30/1 to 30/16

The following Examples were prepared similar as described for Example 30using the appropriate starting materials.

# starting material structure analytical data 30/ 1

¹H-NMR (500 MHz, DMSO-d₆) δ: 13.12 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H),8.07 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.81(d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63-7.60 (m, 1H),7.55-7.47 (m, 2H), 7.42-7.37 (m, 4H), 7.31-7.25 (m, 3H), 7.07 (d, J =5.0 Hz, 1H), 2.24 (s, 3H); MS: 574.8 (M + 1)⁺. 30/ 2

¹H-NMR (500 MHz, CD₃OD) δ: 8.43 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 5.0Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51-7.32 (m, 9H), 7.27 (d, J = 8.5Hz, 2H), 7.22 (s, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 5.0 Hz,1H), 2.22 (s, 3H), 1.62 (s, 6H); MS: 615.0 (M + 1)⁺. 30/ 3

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.75 (s, 1H), 8.75 (s, 1H), 8.66 (d, J =2.0 Hz, 1H), 8.28 d, J = 8.5 Hz, 1H), 8.05-8.02 (m, 2H), 7.84 (d, J =7.5 Hz, 1H), 7.62 (s, 1H), 7.54-7.25 (m, 9H), 7.11 (d, J = 5.0 Hz, 1H),2.23 (s, 3H), 1.61 (s, 6H); MS: 618.1 (M + 1)⁺. 30/ 4

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H),8.02 (d, J = 5.0 Hz, 1H), 7.61-7.44 (m, 5H), 7.42-7.08 (m, 4H),7.07-7.06 (m, 1H), 7.00- 6.94 (m, 2H), 2.39-2.34 (m, 1H), 1.72 (s, 1H),1.44-1.40 (m, 1H), 1.25-1.23 (m, 1H); MS: 540.8 (M + 1)⁺. 30/ 5

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.05 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H),7.98 (d, J = 5.0 Hz, 1H), 7.60-7.46 (m, 5H), 7.40-7.23 (m, 4H), 7.13 (d,J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 5.0 Hz, 1H), 2.56 (t, J =8.0 Hz, 2H), 2.15 (t, J = 7.0 Hz, 2H), 1.74-1.70 (m, 2H); MS: 560.8 (M +1)⁺. 30/ 6

¹H-NMR (500 MHz, CD₃OD) δ: 8.34 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 5.0Hz, 1H), 7.83-7.79 (m, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62-7.58 (m, 1H),7.53-7.42 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H),6.77 (d, J = 7.0 Hz, 1H), 4.54-4.43 (m, 4H), 3.77-3.73 (m, 1H); MS:574.7 (M + 1)⁺. 30/ 7

¹H-NMR (500 MHz, CD₃OD) δ: 8.38 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.0Hz, 1H), 7.51-7.34 (m, 7H), 7.16 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 5.0Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 6.55-6.53 (m, 1H), 6.23 (s, 1H),4.01-3.97 (m, 2H), 3.91-3.88 (m, 2H), 3.54-3.50 (m, 1H); MS: 574.1 (M +1)⁺. 30/ 8

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.26 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 5.5Hz, 1H), 7.64-7.51 (m, 5H), 7.42-7.36 (m, 2H), 7.05 (d, J = 5.0 Hz, 1H),7.02 (d, J = 5.0 Hz, 1H), 6.88 (d, J = 3.5 Hz, 1H), 2.52-2.45 (m, 1H),1.78-1.75 (m, 1H), 1.48-1.42 (m, 1H), 1.24-1.18 (m, 1H); MS: 582.1 (M +18)⁺. 30/ 9

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.25 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 5.0Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.55-7.47 (m, 3H), 7.42-7.36 (m, 3H),7.10 (s, 1H), 7.05 (d, J = 5.0 Hz, 1H), 6.90 (s, 1H), 2.39-2.35 (m, 1H),1.79-1.72 (m, 1H), 1.43-1.38 (m, 1H), 1.25-1.20 (m, 1H); MS: 610.0 (M +18)⁺. 30/ 10

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.29 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H),8.00 (d, J = 5.5 Hz, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.46-7.34 (m, 3H),7.25-7.19 (m, 2H), 7.14-7.10 (m, 2H), 6.99 (d, J = 5.0 Hz, 1H), 3.65 (s,3H), 2.37-2.35 (m, 1H), 1.82-1.75 (m, 1H), 1.45-1.38 (m, 1H), 1.28-1.22(m, 1H); MS: 529.2 (M + 1)⁺. 30/ 11

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.49 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H),7.99 (d, J = 5.0 Hz, 1H), 7.58-7.40 (m, 5H), 7.40-7.32 (m, 2H),7.16-7.13 (m, 1H), 6.98 (d, J = 5.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H),6.52 (d, J = 7.5 Hz, 1H), 6.27 (s, 1H), 3.33-3.28 (m, 2H), 3.21-3.14 (m,3H), 2.21-2.13 (m, 2H); MS: 587.8 (M + 1)⁺. 30/ 12

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.35 (br s, 1H), 8.13 (d, J = 8.0 Hz, 1H),8.04 (s, 1H), 7.52-7.39 (m, 3H), 7.27-7.13 (m, 4H), 7.04 (d, J = 5.0 Hz,1H), 2.88-2.83 (m, 1H), 2.41-2.36 (m, 1H), 1.75-1.72 (m, 1H), 1.43-1.39(m, 1H), 1.28-1.25 (m, 1H), 0.99-0.94 (m, 4H); MS: 471.0 (M − 18 + H)⁺.30/ 13

¹H-NMR (500 MHz, CD₃OD) δ: 8.37 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H),7.33-7.30 (m, 1H), 7.27-7.17 (m, 9H), 6.74 (s, 1H), 6.60 (d, J = 5.5 Hz,1H), 2.40-2.36 (m, 1H), 2.35 (s, 3H), 1.76-1.72 (m, 1H), 1.51-1.48 (m,1H), 1.17-1.13 (m, 1H); MS: 548.0 (M + 1)⁺. 30/ 14

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.38 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H),7.49- 7.45 (m, 1H), 7.36-7.13 (m, 8H), 7.15 (d, J = 7.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.48- 6.46 (m, 1H), 2.39-2.34 (m, 1H), 2.31 (s, 3H),1.73-1.69 (m, 1H), 1.45-1.40 (m, 1H), 1.27-1.23 (m, 1H); MS: 530.0 (M −1)⁺. 30/ 15

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.35 (br s, 1H), 8.25 (d, J = 8.5 Hz, 1H),7.88-7.85 (m, 1H), 7.57-7.34 (m, 8H), 7.32-7.18 (m, 3H), 7.06 (s, 1H),6.84 (s, 1H), 2.32-2.29 (m, 4H), 1.64-1.61 (m, 1H), 1.43-1.39 (m, 1H),1.19-1.16 (m, 1H); MS: 549.0 (M − 1)⁻. 30/ 16

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.32- 8.28 (m, 1H), 7.94-7.88 (m, 3H),7.65- 7.24 (m, 12H), 7.04-6.85 (m, 2H), 5.19 (br s, 1H), 1.23 (s, 6H);MS: 663.0 (M − 1)⁻

Example 31

3-((6-(1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-1H-indol-2-yl)pyridin-2-yl)oxy)propanoicAcid (31)

A solution of compound 1/62 (110 mg, 0.19 mmol) in 4N HCl in dioxane (30mL) was stirred at rt overnight. The solvent was removed, EA (20 mL) wasadded and the mixture was washed with water (10 mL) and brine (10 mL).The organic layer was dried over Na₂SO₄, concentrated and purified byprep-HPLC to give compound 31 as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ: 12.38 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.02 (d, J=5.0 Hz,1H), 7.94-7.91 (m, 2H), 7.77-7.65 (m, 3H), 7.54-7.42 (m, 1H), 7.41-7.37(m, 2H), 7.13 (d, J=6.8 Hz, 1H), 7.00 (d, J=4.8 Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 4.32 (t, J=6.4 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H); MS: 563.8(M+1)⁺.

Example 32

3′-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)-N-(methylsulfonyl)-[1,1′-biphenyl]-3-carboxamide(32)

A cloudy solution of compound 30/1 (100 mg, 0.17 mmol),methanesulfonamide (17 mg, 0.17 mmol), DMAP (21 mg, 0.17 mmol) and EDCl(50 mg, 0.26 mmol) in DMF (4 mL) was stirred for 14 h at rt. The productwas purified from the mixture by prep-HPLC to give compound 32 as awhite solid. ¹H-NMR (500 MHz, DMSO-d₆) δ:12.30 (s, 1H), 8.31-7.92 (m,4H), 7.83 (t, J=7.5 Hz, 2H), 7.65-7.62 (m, 2H), 7.55-7.49 (m, 2H),7.42-7.39 (m, 4H), 7.30-7.26 (m, 3H), 7.07 (d, J=2.5 Hz, 1H), 3.42 (s,3H), 2.25 (s, 3H); MS: 652.1 (M+1)⁺.

Example 32/1 to 32/5

The following Examples were prepared similar as described for Example 32using the appropriate starting materials.

# starting material structure analytical data 32/ 1

¹H-NMR (500 MHz, DMSO-d₆) δ: 12.09 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H),8.01 (d, J = 5.0 Hz, 1H), 7.62- 7.59 (m, 2H), 7.54-7.23 (m, 7H),7.10-6.96 (m, 3H), 3.28 (s, 1H), 2.46-2.42 (m, 1H), 2.09-2.06 (m, 1H),1.51-1.46 (m, 1H), 1.35-1.32 (m, 1H); MS: 658.0 (M + Na)⁺. 32/ 2

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.27 (dd, J = 9.1, 4.4 Hz, 1H), 7.98 (d, J= 5.1 Hz, 1H), 7.46-7.28 (m, 5H), 7.20-7.07 (m, 2H), 6.94 (d, J = 5.1Hz, 1H), 6.57-6.48 (m, 2H), 6.24 (s, 1H), 3.95 (t, J = 7.5 Hz, 2H),3.89-3.80 (m, 1H), 3.72 (t, J = 6.2 Hz, 2H), 3.52 (s, 3H), 2.87 (s, 3H),2.33 (s, 3H), 1.34 (s, 6H); MS: 685.0 (M + 1)⁺. 32/ 3

32/ 4

¹H-NMR (500 MHz, DMSO-d₆ ) δ: 12.32 (s, 1H), 8.31-8.28 (m, 1H), 8.11 (d,J = 1.5 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.99-7.97 (m, 2H), 7.55-.35(m, 4H), 7.41-7.33 (m, 3H), 7.26-7.18 (m, 3H), 7.07-7.03 (m, 2H), 3.38(s, 3H), 2.22 (s, 3H); MS: 701.9 (M − 1)⁻. 32/ 5

¹H-NMR (500 MHz, CD₃OD) δ: 8.44 (dd, J = 9.0, 4.0 Hz, 1H), 8.08-8.04 (m,3H), 7.93 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (t, J = 8.3 Hz, 1H), 7.55-7.32 (m, 9H), 7.12 (s, 1H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 6.69 (t, J =55.5 Hz, 1H), 3.36 (s, 3H); MS: 756.8 (M − 1)⁻.

Example 33

Methyl3′-(3-(2-cyanothioahen-3-yl)-5-fluoro-7-hydroxy-1-tosyl-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(33)

To a solution of compound 1/101 (120 mg, 0.19 mmol) in DCM (6 mL) at−78° C. was slowly added BBr₃ (10 mL, 1M in DCM). The mixture wasstirred at this temperature for 40 min and at rt for 1 h, quenched withH₂O (20 mL) and extracted with EA (2×100 mL). The combined organic layerwas washed with brine (20 mL), dried over Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC (EA:PE=1:1) to afford compound 33 as ayellow oil.

Example 34

Step 1: Ethyl2-((3′-(3-(2-cyanothioahen-3-yl)-1-tosyl-1H-indol-2-yl)-5-fluoro-4-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)acetate(34a)

To a solution of compound 1 (290 mg, 0.54 mmol) in dioxane (15 mL) wasadded compound P3-1 (193 mg, 0.54 mmol), B₂Pin₂ (166 mg, 0.65 mmol),Pd(dppf)Cl₂ (39 mg, 0.05 mmol) and KOAc (107 mg, 1.09 mmol). The mixturewas stirred at 100° C. overnight. After cooling to rt the mixture wasfiltered, the filtrate was concentrated und reduced pressure and theresidue was purified by prep-TLC (EA:PE=1:1) to afford compound 34a as ayellow oil.

Step 2:2-((3′-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)-5-fluoro-4-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)aceticAcid (34)

To a solution of compound 34a (90 mg, 0.12 mmol) in EtOH (10 mL) wasadded LiOH.H₂O (26 mg, 0.62 mmol) and the mixture was stirred at rt for1.5 h. Then the EtOH was removed, water was added and the pH wasadjusted to <4 by addition of 2N HCl. The mixture was extracted with EA(3×40 mL) and the combined organic layer was washed with brine (10 mL),dried over Na₂SO₄, concentrated and purified by prep-HPLC to affordcompound 34 as a white solid. ¹H-NMR (500 MHz, CD₃OD) δ: 8.42 (d, J=8.5Hz, 1H), 7.99 (s, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H),7.64-7.30 (m, 9H), 7.20 (d, J=8.5 Hz, 2H), 7.03 (d, J=5.0 Hz, 1H), 5.11(s, 2H), 4.50 (s, 2H), 2.29 (s. 3H); MS: 718.1 (M+18)⁺.

Example 35

Step 1: Methyl3′-((2-amino-5-fluorophenyl)ethynyl-2-chloro-[1,1′-biphenyl]-4-carboxylate(35a)

To a solution of compound P5 (5.00 g, 15.4 mmol) in TEA (60 mL) wasadded Pd(PPh₃)₄ (710 mg, 0.61 mmol), CuI (175 mg, 0.92 mmol), PPh₃ (241mg, 0.92 mmol), and 2-ethynyl-4-fluoroaniline (2.70 g, 20.0 mmol). Themixture was stirred at 60° C. under N₂ overnight. After cooling to rtthe mixture was filtered, the filtrate was concentrated and the residuewas purified by FCC (PE:EA=2:1) to give compound 35a as a light yellowsolid.

Step 2: Methyl2-chloro-3′-((5-fluoro-2-(2.2.2-trifluoroacetamido)phenyl)ethynyl)-[1,1′-biphenyl]-4-carboxylate(35b)

To a solution of compound 35a (300 mg, 0.79 mmol) in DCM (15 mL) wasadded TFAA (199 mg, 0.95 mmol) and TEA (120 mg, 1.19 mmol). The mixturewas stirred at rt for 15 min, then DCM (20 mL) was added and the mixturewas washed with H₂O (2×10 mL) and brine (20 mL). The organic layer wasdried over Na₂SO₄ and concentrated to dryness to afford crude compound35b as a yellow solid.

Step 3: Methyl2-chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(35c)

To a solution of compound 35b (320 mg, 0.67 mmol) in ACN (20 mL) wasadded 3-bromo-thiophene-2-carbonitrile (190 mg, 1.01 mmol), K₂CO₃ (185mg, 1.34 mmol), and Pd(PPh₃)₄ (77 mg, 67 μmol) under N₂ and the mixturewas stirred at 100° C. for 2 h, cooled to rt, poured into EA (20 mL) andwashed with H₂O (2×20 mL) and brine (20 mL). The organic layer was driedover Na₂SO₄, concentrated and purified by FCC (EA:PE=1:3) to givecompound 35c as a yellow solid.

Step 4: Methyl2-chloro-3′-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(35)

To a solution of compound 35c (200 mg, 0.41 mmol) in THF (8 mL) at 0° C.was added NaH (60% in mineral oil, 50 mg, 1.23 mmol) and6-(trifluoromethyl)pyridine-3-sulfonyl chloride (201 mg, 0.82 mmol). Themixture was stirred at rt for 1 h and poured into cold sat. aq. NH₄Cl(50 mL). The mixture was extracted with EA (2×50 mL) and washed withbrine (20 mL). The combined organic layer was dried over Na₂SO₄,concentrated and purified by prep-TLC (EA:PE=1:3) to give compound 35 asa yellow solid.

Example 35/1 to 35/2

The following Examples were prepared similar as described for Example 35using the appropriate starting materials.

# starting material structure 35/1

35/2

Example 36

5-(3-(3-(2-Cyanothiophen-3-yl)-5-fluoro-1-tosyl-1/indol-2-yl)phenyl)-4-methylpicolinicAcid (36)

To a stirred solution of compound 2/13 (150 mg, 0.24 mmol) in THF (10mL) at rt was added 1N LiOH (1 mL) and stirring was continued at rt for2 h. The mixture was extracted with EA (100 mL), the organic layer waswashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by prep-HPLC to give compound 36 as a white solid. ¹H-NMR (500MHz, DMSO-d₆) δ: 8.39 (s, 1H), 8.28 (dd, J=10.0, 4.5 Hz, 1H), 8.05 (d,J=5.0 Hz, 1H), 8.01 (s, 1H), 7.57-7.51 (m, 2H), 7.42-7.36 (m, 4H), 7.27(d, J=8.5 Hz, 2H), 7.20-7.18 (m, 1H), 7.13 (s, 1H), 7.06 (d, J=5.0 Hz,1H), 2.24 (s, 3H), 2.19 (s, 3H); MS: 606.0 (M−1)⁻.

Example 36/1

The following Example was prepared similar as described for Example 36using the appropriate starting material.

# starting material structure analytical data 36/1

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.30- 8.27 (m, 1H), 8.04 (d, J = 5.0 Hz,1H), 7.91 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.54-7.48 (m,2H), 7.40-7.36 (m, 4H), 7.28-7.26 (m, 2H), 7.19-7.17 (m, 1H), 7.12 (s,1H), 7.05 (d, J = 5.0 Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H); MS: 607.8(M + 1)⁺.

Example 37

3-(2-(2′-Chloro-4′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-5-fluoro-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile(37)

To a stirred solution of compound P2/15 (150 mg, 0.17 mmol) in acetone(10 mL) at rt was added 1N HCl (1 mL) and stirring was continued for 2h. Water was added and the mixture was extracted with EA (100 mL). Theorganic layer was washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by prep-HPLC to give compound 37 as a whitesolid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.31-8.28 (m, 1H), 8.19 (s, 1H),8.11-8.09 (m, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.59-7.56 (m, 3H), 7.47-7.20(m, 7H), 7.11 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 2.21 (s, 3H); MS: 649.0(M−1).

Example 37/1

The following Example was prepared similar as described for Example 37using the appropriate starting material.

# starting material structure analytical data 37/ 1

¹H-NMR (500 MHz, DMSO-d₆) δ: 8.33-8.30 (m, 1H), 8.16 (s, 1H), 8.02-7.76(m, 5H), 7.61 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.41-7.37 (m, 3H),7.30-7.26 (m, 3H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.07 (d, J = 5.0 Hz,1H), 3.71 (s, 3H), 2.24 (s, 3H); MS: 694.0 (M + 1)⁺.

Example 38

rel-Methyl(2R,4R)-1-(3-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)phenyl)-2-methylpiperidine-4-carboxylate(38)

To a solution of compound 1 (500 mg, 0.91 mmol) in toluene (15 mL) wasadded rel-methyl (2R,4R)-2-methylpiperidine-4-carboxylate (215 mg, 1.36mmol), Cs₂CO₃ (869 mg, 2.27 mmol), Pd₂(dba)₃ (83 mg, 90 μmol) and BINAP(113 mg, 0.18 mmol) under N₂. The mixture was stirred at 100° C.overnight, cooled to rt, poured into EA (200 mL) and washed with H₂O (30mL) and brine (30 mL). The organic layer was dried over Na₂SO₄,concentrated and purified by prep-TLC (EA:PE=1:1) to give compound 38 asa yellow oil.

Example 38/1

The following Example was prepared similar as described for Example 38using the appropriate starting materials.

# starting materials structure 38/1

Example 39

Methyl2-chloro-3′-(1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-3-(2-(3-fluoroazetidin-3-yl)phenyl)-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(39)

To a solution of compound 1/114 (30 mg, 40 μmol) in DCM (2 mL) was addedTFA (0.2 mL) and the mixture was stirred at rt for 4 h. The mixture waspoured into water and the pH was adjusted to 8 with sat. aq. NaHCO₃.Then the mixture was extracted with EA and the organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to dryness to givecompound 39 as a yellow solid.

Example 40

Methyl2-chloro-3-(1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-3-(2-(3-fluoro-1-methyl-azetidin-3-yl)phenyl)-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(40)

To a solution of compound 39 (27 mg, 40 μmol) in MeOH (2 mL) was addedformaldehyde (0.2 mL) and the mixture was stirred at rt for 1 h. ThenNaBH(OAc)₃ (82 mg, 0.37 mmol) was added and the mixture was stirred atrt for overnight. Water (40 mL) was added and the mixture was extractedwith DCM (3×20 mL). The combined organic layer was washed with brine (30mL), dried over Na₂SO₄, filtered, concentrated and purified by FCC(PE:EA=1:1) to afford compound 40 as a yellow solid.

Example 41/1 and Example 41/2

Separated Atropisomers of2-chloro-3′-(3-(2-cyano-6-methylphenyl)-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicAcid (41/1 and 41/2)

Compound 11/36 (300 mg) was separated by chiral-HPLC (instrument:Gilson-281; column: IE 20*250, 10 μm; mobile phase: n-hexane (0.1%DEA):EtOH (0.1% DEA)=55:45; run time per injection: 14 min; injection:0.4 mL; sample solution: 75 mg in 3 mL MeOH) to give as first elutingisomer (retention time: 10.28 min) compound 41/1 and as second elutingisomer (retention time: 14.35 min) compound 41/2. NMR corresponds withExample 11/36; MS: 669.0 (M−1)⁻.

Example 42

Step 1: Methyl 4-(N-(4-fluoro-2-iodophenyl)sulfamoyl)benzoate (42a)

To a solution of 4-fluoro-2-iodoaniline (2.00 g, 8.43 mmol) in pyridine(10 mL) was added methyl 4-(chlorosulfonyl)benzoate (2.20 g, 9.40 mmol).The mixture was stirred at rt overnight. Brine (40 mL) was added and theformed solid was filtered off, washed with EA (30 mL) and water (30 mL).The crude product was lyophilized to give compound 42a as a white solid.

Step 2:N-(4-Fluoro-2-iodophenyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide(42b)

To a solution of compound 42a (3.50 g, 8.04 mmol) in THF (30 mL) wasadded a solution of MeMgBr (2.0M in THF, 20 mL, 40.0 mmol) at −78° C.slowly during 20 min. The mixture was stirred at −78° C. for 6 h beforethe mixture was allowed to warm to rt. Saturated aq. NH₄Cl (50 mL) wasadded and the resulting mixture was extracted with EA (3×50 mL). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuoto afford compound 42b as a white solid.

Step 3: Methyl2-chloro-3′-((5-fluoro-2-((4-(2-hydroxypropan-2-yl)phenyl)sulfonamido)phenyl)-ethynyl)-[1,1′-biphenyl]-4-carboxylate(42c)

To a solution of compound 42b (1.30 g, 2.98 mmol) and compound P30 (740mg, 2.74 mmol) in dry THF (20 ml) were added CuI (23 mg, 0.12 mmol),Pd(PPh₃)₂Cl₂ (130 mg) and TEA (830 mg, 8.22 mmol). The mixture wasstirred at 0° C. for 30 min under argon and then stirred at rtovernight, diluted with water (30 ml) and extracted with EA (3×40 mL).The combined organic layer was washed by brine (2×50 mL), dried overNa₂SO₄, filtered, concentrated and purified by FCC (PE:EA=5:1) to givecompound 42c as a pale yellow solid.

Stet 4: Methyl2-chloro-3′-(5-fluoro-1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)-3-iodo-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(42d)

To a solution of compound 42c (500 mg, 0.86 mmol) and K₂CO₃ (368 mg,2.67 mmol) in ACN (30 ml) was added NIS (608 mg, 2.67 mmol) at −10° C.under argon. The mixture was allowed to warm to rt during 30 min andstirred overnight. The mixture was washed with aq. sat. Na₂S₂O₃ (3×20ml) and extracted with DCM (2×20 mL). The combined organic layer wasdried over Na₂SO₄, filtered, concentrated and purified by prep-HPLC togive compound 42d as a white solid.

Step 5: Methyl2-chloro-3′-(3-(2-cyanophenyl)-5-fluoro-1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(42)

To a solution of compound 42d (350 mg, 0.49 mmol),(2-cyanophenyl)boronic Acid (217 mg, 1.47 mmol) and K₂CO₃ (210 mg, 1.47mmol) in a mixture of dioxane and H₂O (15 mL, 10:1) was addedPd(dppf)Cl₂ (45 mg) under argon. The mixture was stirred at 60° C. for 4h, cooled, quenched with water (20 mL) and extracted with EA (3×20 mL).The combined organic layer was washed with brine (20 mL), dried overNa₂SO₄, filtered, concentrated and purified by prep-TLC (PE:EA=8:5) togive compound 42 as a yellow solid.

Example 43/1 and Example 43/2

Separated Isomers methyl(1s,4s)-4-(3-(3-(2,6-dicyanophenyl-1-((4-(difluoro-methyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)phenyl)cyclohexane-1-carboxylate(43/1) and methyl(1r,4r)-4-(3-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1Hindol-2-yl)phenyl)cyclohexane-1-carboxylate (43/2)

To a solution of compound 8/4 (665 mg, 1.00 mmol) in MeOH (10 mL) wasadded Pd/C (100 mg). The mixture was stirred at rt for 16 h under H₂.The catalyst was filtered off and washed with MeOH (15 mL). The combinedfiltrates were concentrated. The residue was purified by prep-TLC(EA:PE=1:3) to give the two separated compounds 43/1 and 43/2 as whitesolids, respectively.

Example 44

Step 1: Methyl3′-((2-amino-4-fluoro-5-methoxyphenyl)ethynyl)-2-chloro-[1,1′-biphenyl]-4-carboxylate(44a)

To a solution of compound P30 (1.39 g, 5.10 mmol) in TEA (20 mL) wasadded Pd(PPh₃)₄ (237 mg, 205 μmol), CuI (78 mg, 0.41 mmol), PPh₃ (108mg, 0.41 mmol) and 2-bromo-5-fluoro-4-methoxyaniline (1.34 g, 6.12mmol). The mixture was stirred at 60° C. under N₂ overnight. Thereaction was cooled, filtered, concentrated and purified by FCC(PE:EA=1:1) to give compound 44a as a light yellow solid.

Step 2: Methyl2-chloro-3′-((2-((4-(difluoromethyl)phenyl)sulfonamido)-4-fluoro-5-methoxy-phenyl)ethynyl-[1,1′-biphenyl]-4-carboxylate(44b)

To a solution of compound 44a (818 mg, 2.00 mmol) in DCM (10 mL) wasadded 4-(difluoromethyl)benzene-1-sulfonyl chloride (542 mg, 2.40 mmol),pyridine (316 mg, 4.00 mmol) and DMAP (89 mg). The mixture was stirredat rt overnight, then DCM (20 mL) was added and the mixture was washedwith 2N aq. HCl (2×20 mL) and brine (40 mL). The organic layer was driedover Na₂SO₄, concentrated and purified by FCC (PE:DCM=1:1) to givecompound 44b as a white solid.

Step 3: Methyl2-chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-6-fluoro-5-methoxy-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylate(44c)

To a solution of compound 44b (599 mg, 1.00 mmol) in dioxane (5 mL) wasadded 2-bromo-isophthalonitrile (310 mg, 1.50 mmol), K₂CO₃ (276 mg, 2.00mmol) and Pd(PPh₃)₄ (47 mg, 40 μmol) under N₂. The mixture was stirredat 90° C. for 4 h under N₂. Upon completion, the mixture was cooled tort, poured into EA (20 mL) and washed with H₂O (2×20 mL) and brine (20mL). The organic layer was dried over Na₂SO₄, concentrated and purifiedby FCC (EA:PE=1:1) to give compound 44c as a yellow solid.

Step 4:2-Chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-6-fluoro-5-hydroxy-1H-indol-2-yl)-[1,1′-biphenyl]-4-carboxylicAcid (44)

To a solution of compound 44c (390 mg, 0.53 mmol) in CCl₄ (10 mL) wasadded iodotrimethyl-silane (5 mL) and NaI (159 mg, 1.06 mmol) and themixture was stirred at 85° C. overnight. The solvent was removed and theresidue was partitioned between sat. aq. NaS₂O₃ and EA. The aq. phasewas again extracted with EA (3×20 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by prep-HPLC to afford compound 44 as a white solid. ¹H-NMR(400 MHz, CD₃D) δ: 8.12 (d, J=11.7 Hz, 1H), 8.10-7.93 (m, 4H), 7.70 (t,J=7.9 Hz, 1H), 7.58-7.29 (m, 8H), 7.00 (s, 1H), 6.83-6.48 (m, 2H). MS:696.0 (M−1)⁻.

Example 45

2-Chloro-3′-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-hydroxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-[1,1′-biphenyl]-4-carboxylicAcid (45)

If one were to treat a solution of compound 29/3 in ACN (10 mL) withchlorotrimethylsilane and sodium iodide under reflux one would obtaincompound 45.

If one were to follow the procedures described above using appropriatebuilding blocks, the following compounds can be prepared:

Compound Stock Solutions

The tested compounds were usually dissolved, tested and stored as 20 mMstock solutions in DMSO. Since sulfonyl acetic acid derivatives tend todecarboxylate under these conditions, these stock solutions wereprepared, tested and stored as 20 mM DMSO stock solutions containing 100mM trifluoroacetic Acid (5 equivalents). Sulfonyl acetic acidderivatives are shelf stable as solid at rt for long time as reported byGriesbrecht et al. (Synlett 2010:374) or Faucher et al. (J. Med. Chem.2004; 47:18).

TR-FRETß Activity Assay

Recombinant GST-LXRPβ ligand-binding domain (LBD; amino acids 156-461;NP009052; SEQ ID NO:4) was expressed in E. coli and purified viagluthatione-sepharose affinity chromatography. N-terminally biotinylatedNCoA3 coactivator peptide (SEQ ID NO:7) was chemically synthesized(Eurogentec). Assays were done in 384 well format (final assay volume of25 μL/well) in a Tris/HCl buffer (pH 6.8) containing KCl, bovine serumalbumin, Triton-X-100 and 1 μM 24(S)-25-epoxycholesterol asLXR-prestimulating agonist. Assay buffer was provided and test articles(potential LXR inverse agonists) were titrated to yield final assayconcentrations of 50 μM, 16.7 μM, 5.6 μM, 1.9 μM, 0.6 μM, 0.2 μM, 0.07μM, 0.02 μM, 0.007 μM, 0.002 μM with one vehicle control. Finally, adetection mix was added containing anti GST-Tb cryptate (CisBio;610SAXLB) and Streptavidin-XL665 (CisBio; 610SAXLB) as fluorescent donorand acceptor, respectively, as well as the coactivator peptide andLXRβ-LBD protein (SEQ ID NO:4). The reaction was mixed thoroughly,equilibrated for 1 h at 4° C. and vicinity of LXRs and coactivatorpeptide was detected by measurement of fluorescence in a VictorX4multiplate reader (PerkinElmer Life Science) using 340 nm as excitationand 615 and 665 nm as emission wavelengths. Assays were performed intriplicates.

Final Assay Concentrations of Components:

240 mM KCl, 1 μg/μL BSA, 0.002% Triton-X-100, 125 μg/μL anti GST-Tbcryptate, 2.5 ng/μL Streptavidin-XL665, coactivator peptide (400 nM),LXRβ protein (530 μg/mL, i.e. 76 nM).

LXR Gal4 Reporter Transient Transfection Assays

LXRα and LXRβ activity status was determined via detection ofinteraction with coactivator and corepressor proteins in mammaliantwo-hybrid experiments (M2H). For this, via transient transfection thefull length (FL) proteins of LXRα (amino acids 1-447; NP005684; SEQ IDNO:1) or LXRβ-(amino acids 1-461; NP009052; SEQ ID NO:2) or theligand-binding domains (LBD) of LXRα (amino acids 155-447 SEQ ID NO:3)or LXRβ (amino acids 156-461; SEQ ID NO:4) were expressed from pCMV-AD(Stratagene) as fusions to the transcriptional activation domain ofNFkB. As cofactors, domains of either the steroid receptor coactivator 1(SRC1; amino acids 552-887; SEQ ID NO:5) or of the corepressor NCoR(amino acids 1906-2312; NP006302; SEQ ID NO:6) were expressed as fusionsto the DNA binding domain of the yeast transcription factor GAL4 (frompCMV-BD; Stratagene). Interaction was monitored via activation of acoexpressed Firefly Luciferase Reporter gene under control of a promotercontaining repetitive GAL4 response elements (vector pFRLuc;Stratagene). Transfection efficiency was controlled via cotransfectionof constitutively active pRL-CMV Renila reniformis luciferase reporter(Promega). HEK293 cells were grown in minimum essential medium (MEM)with 2 mM L-glutamine and Earle's balanced salt solution supplementedwith 8.3% fetal bovine serum, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, at 37° C. in 5% CO₂. 3.5×10⁴ cells/well were plated in96-well cell culture plates in growth medium supplemented with 8.3%fetal bovine serum for 16-20 h to ˜90% confluency. For transfection,medium was taken off and LXR and cofactor expressing plasmids as well asthe reporter plasmids are added in 30 μL OPTIMEM/well includingpolyethylene-imine (PEI) as vehicle. Typical amounts of plasmidstransfected/well: pCMV-AD-LXR (5 ng), pCMV-BD-cofactor (5 ng), pFR-Luc(100 ng), pRL-CMV (0.5 ng). Compound stocks were prepared in DMSO,prediluted in MEM to a total volume of 120 μL, and added 4 h afteraddition of the transfection mixture (final vehicle concentration notexceeding 0.2%). Cells were incubated for additional 16 h, lysed for 10min in 1× Passive Lysis Buffer (Promega) and Firefly and Renillaluciferase activities were measured sequentially in the same cellextract using buffers containing D-luciferine and coelenterazine,respectively. Measurements of luminescence were done in aBMG-luminometer.

Materials Company Cat.No. HEK293 cells DSMZ ACC305 MEM Sigma-AldrichM2279 OPTIMEM LifeTechnologies 11058-021 FCS Sigma-Aldrich F7542Glutamax Invitrogen 35050038 Pen/Strep Sigma Aldrich P4333 SodiumPyruvate Sigma Aldrich S8636 Non Essential Amino Acids Sigma AldrichM7145 Trypsin Sigma-Aldrich T3924 PBS Sigma Aldrich D8537 PEI SigmaAldrich 40.872-7 Passive Lysis Buffer (5x) Promega E1941 D-LuciferinePJK 260150 Coelentrazine PJK 26035

TABLE 1 LXR activity data LBD-M2H LBD-M2H FL-M2H FL-M2H Ex. # FRETβGal4α Gal4β Gal4α Gal4β  1/23 C D D  1/26 B C D  1/27 B C D  1/28 B C D 1/39 A B —  1/40 B C D  1/41 B C D  1/42 B D D  1/122 C D D  1/139 C DD  2 C D D 2/1 C C C 2/2 C C C  2/16 D D D  2/18 C C D  3 D D D 3/1 C CC 3/2 B C D 3/3 B C C 3/4 C C D 3/5 C C C 3/6 B C C 3/7 B — D 3/8 B C D3/9 B C D  3/10 C C D  3/11 B C —  3/12 C D D  3/13 B D D  3/14 B C C 3/15 B — —  3/16 B C C  3/17 B C D  3/18 B C D  3/19 B C C  3/20 B C D 3/21 C D D  3/22 D D D  3/23 C D D  3/24 D D D D  3/25 B C D  3/26 B CD  3/27 B C C  3/28 A — B  3/29 B — —  3/30 C D D  3/31 C C C  3/32 C CD  3/33 B C D  3/34 C C D  3/35 C C D  3/36 B C C  3/37 C D D  3/38 C DD  3/39 C C D  3/40 B C D  3/41 B D D  3/42 B C D C D  3/43 B C C C D 3/44 B D D D D  3/45 B C C  3/46 C D D D D  3/47 C D D  3/48 C D D 3/49 C D D  3/50 C D D  3/51 B C C  3/52 C C C  3/53 D D D  3/54 C D D 3/55 C D D  3/56 D D D  3/57 C D D  3/58 B D D  3/59 D D D  3/60 C D D 3/61 C C C  3/62 C C D  3/63 D D D  3/64 C D D  3/65 C D D  3/66 B C C 3/67 C C C  3/68 C D D  3/69 C C C  3/70 C C C  3/71 D D D  3/72 D D D 3/73 D D D  4 B D C 4/1 B C D 4/2 B C C 4/3 B D D  5 C B B 5/1 C B C5/2 C C C 5/3 C D 5/4 B C D 5/5 C C C 5/6 C D D 5/7 C C D 5/8 C C C 5/9C C D  5/10 B C C  6 C D D 6/1 C D D 6/2 C D D 6/3 D D D  8 C C D 8/1 CD D 8/3 C C D 8/7 C C D 8/8 D D D 10 C D C 10/1  D D D 10/2  D D D 10/3 D D D 10/4  D C D 11 D D D 11/1  D D D 11/2  D D D 11/3  D D D 11/4  C DD 11/5  D D D 11/6  D D D 11/7  D D D 11/8  D D D 11/9  D D D 11/10 D DD 11/11 D D D 11/12 D D D 11/13 D D D 11/14 D D D 11/15 D D D 11/16 C DD 11/17 D D D 11/18 C D D 11/19 C D D 11/20 C D D 11/21 D D D 11/22 D DD 11/23 D D D 11/24 C C C 11/25 C C D 11/26 D D D 11/27 D D D 11/28 D DD 11/29 D D D 11/30 D D D 11/31 D D D 11/32 D D D 11/33 D D D 11/34 D DD 11/35 D D D 11/36 D D D 11/37 D D D 11/38 D D D C11/39   C D D 11/40 CD D 11/41 D D D 11/42 A C C 11/43 C C C 11/44 D D D 11/45 D D D 11/46 DD D 11/47 C C C C11/48   D D D 11/49 D D D 11/50 D D D 11/51 D D D 11/52D D D 11/53 D D D 11/54 D D D 11/55 D D D 11/56 D D D 11/57 D D D 11/58D D D 11/59 D D D 11/60 D D 11/61 C D D 11/62 C D D 11/63 C D D 11/64 CD D 11/65 D D D 11/66 C D D 11/67 C D D 11/68 D D D 11/69 D D D 12 C D D12/1  C D D 12/2  C D D 12/3  C D D 12/4  C D D 12/5  D D D 12/6  B C B12/7  C C C 12/8  B C C 12/9  C C C 12/10 D D D 13 C D D 13/1  B D D 15A B A 15/1  B C C 15/2  A C C 15/3  A — — 15/4  B C D 15/5  B D D 15/6 B — C 17 A — B 19 A — — 20 C D D 20/2  B C D 20/3  C D D 20/4  B D D20/5  B C C 20/6  C C D 20/7  B C D 20/11 C D D 20/12 B D D 20/13 C D D20/14 C D D 20/15 C — C 20/16 B C C 20/17 — — C 20/18 — C D 20/19 A C C20/20 B B C 20/21 B C D 20/22 C C C 20/23 B C C 21 A — B 21/1  B B B21/2  B B B 21/3  D D D 22 B C C 23 A C C 23/1  B — D 23/2  C D D 23/3 C D D 24 B C D 25 B C D 26 C D D 26/1  B C D 27 B C 27/1  B — — 27/2  B27/3  A — — 28 B B C 30 C D D 30/1  C C D 30/2  B C C 30/3  C C 30/4  BC D 30/5  B C D 30/6  B C C 30/7  C D D 30/8  B C C 30/9  B C D 30/10 A— 30/11 C C D 30/12 B B C 30/13 C C D 30/14 B C C 30/15 B C C 30/16 B CC 31 B C C 32 C C C 32/1  C C D 32/2  C C C 32/4  D D D 32/5  D D D 36 BC C 36/1  C D D 37 C D D 37/1  C C C 41/1  D D D 41/2  D D D 44 C D DRanges (EC₅₀): no activity measured; A: >10 μM, B: 1 μM to <10 μM, C:100 nM to <1 μM, D: <100 nM; italic numbers indicate that efficacy(compared to GW2033) is below 40%.

Pharmacokinetics

The pharmacokinetics of the compounds was assessed in mice after singledosing and oral administrations. Blood/plasma and liver exposure wasmeasured via LC-MS.

The study design was as follows:

Animals: C57/bl6/J (Janvier) males

Diet: standard rodent chow

Dose: 20 mg/kg

Animal handling: animals were withdrawn from food at least 12 h beforeadministration

Design: single dose oral administration, n=3 animals per group

Sacrifice: at stated time point (4, 12 or 24 h) after administration

Bioanalytics: LC-MS of liver and blood/plasma samples

TABLE 2 Study results Example time point blood/plasma liver liver/blood# (h) exposure exposure ratio GSK2033 4 below below — (comparative LLOQLLOQ example) (14.4 ng/mL) (9.6 ng/mL) SR9238 4 below below —(comparative LLOQ LLOQ example)  3/24 4 D C D  3/48 12 below A — LLOQ(1.2 ng/mL)  5/3 4 C C C 8 4 B D B 23/2 4 B D C 30/4 4 C C C 30/7 4 D BD Ranges: blood/plasma exposure: A: >1 μM, B: 300 nM to ≤1 μM, C: 100 nMto <300 nM, D: <100 nM; liver exposure: A: <300 nM, B: 300 nM to ≤1 μM,C: 1 μM to ≤3 μM, D: >3 μM; liver/plasma ratio: A: <3, B: 3 to ≤10, C:10 to ≤30, D: >30;

We confirmed that structurally unrelated LXR inverse agonists GSK2033and SR9238 are not orally bioavailable. We found, that compounds fromthe present invention are orally bioavailable and the target tissueliver was effectively reached by such compounds and a systemic exposure,which is not desired, could be minimized.

Short Term HFD Mouse Model:

The in vivo transcriptional regulation of several LXR target genes byLXR modulators was assessed in mice.

For this, C57BL/6J were purchased from Elevage Janvier (Rennes, France)at the age of 8 weeks. After an acclimation period of two weeks, animalswere preferred on a high fat diet (HFD) (Ssniff Spezialditen GmbH,Germany, Surwit EF D12330 mod, Cat. No. E15771-34), with 60 kcal % fromfat plus 1% (w/w) extra cholesterol (Sigma-Aldrich, St. Louis, Mo.) for5 days. Animals were maintained on this diet during treatment with LXRmodulators. The test compounds were formulated in 0.5%hydroxypropylmethylcellulose (HPMC) and administered in three doses(from 1.5 to 20 mg/kg each) by oral gavage according to the followingschedule: on day one, animals received treatment in the morning and theevening (ca. 17:00), on day two animals received the final treatment inthe morning after a 4 h fast and were sacrificed 4 h thereafter. Animalwork was conducted according to the national guidelines for animal carein Germany.

Upon termination, liver was collected, dipped in ice cold PBS for 30seconds and cut into appropriate pieces. Pieces were snap frozen inliquid nitrogen and stored at −80° C. For the clinical chemistryanalysis from plasma, alanine aminotransferase (ALT, IU/mL), cholesterol(CHOL, mg/dL) and triglycerides (TG, mg/dL) were determined using afully-automated bench top analyzer (Respons®910, DiaSys Greiner GmbH,Flacht, Germany) with system kits provided by the manufacturer.

Analysis of gene expression in liver tissue. To obtain total RNA fromfrozen liver tissue, samples (25 mg liver tissue) were first homogenizedwith RLA buffer (4M guanidin thiocyanate, 10 mM Tris, 0.97% w:vβ-mercapto-ethanol). RNA was prepared using a SV 96 total RNA Isolationsystem (Promega, Madison, Wis., USA) following the manufacturer'sinstructions. cDNAs were synthesized from 0.8-1 μg of total RNA usingAll-in-One cDNA Supermix reverse transcriptase (Absource Diagnostics,Munich, Germany). Quantitative PCR was performed and analyzed usingPrime time Gene expression master mix (Integrated DNA Technologies,Coralville, Iowa, USA) and a 384-format ABI 7900HT Sequence DetectionSystem (Applied Biosystems, Foster City, USA). The expression of thefollowing genes was analysed: Stearoyl-CoA desaturasel (Scd1), fattyacid synthase (Fas) and sterol regulatory element-binding protein1(Srebp1). Specific primer and probe sequences (commercially available)are listed in Table 3. qPCR was conducted at 95° C. for 3 min, followedby 40 cycles of 95° C. for 15 s and 60° C. for 30 s. All samples wererun in duplicates from the same RT-reaction. Gene expression wasexpressed in arbitrary units and normalized relative to the mRNA of thehousekeeping gene TATA box binding protein (Tbp) using the comparativeCt method.

TABLE 3 Primers used for quantitative PCR Gene Forward PrimerReverse Primer Sequence Probe Fasn CCCCTCTGTTAATTGGC TTGTGGAAGTGCAGGTCAGGCTCAGGGTGTCCC TCC (SEQ ID NO: TAGG (SEQ ID NO: ATGTT (SEQ ID NO: 8)9) 10) Scd1 CTGACCTGAAAGCCGA AGAAGGTGCTAACGAA TGTTTACAAAAGTCTCGC GAAGCAGG CCCAGCA (SEQ ID NO: 11) (SEQ ID NO: 12) (SEQ ID NO: 13) Srebp1cCCATCGACTACATCCGC GCCCTCCATAGACACA TCTCCTGCTTGAGCTTCT TTC (SEQ ID NO:TCTG (SEQ ID NO: GGTTGC (SEQ ID NO: 14) 15) 16) Tbp CACCAATGACTCCTATGCAAGTTTACAGCCAAG ACTCCTGCCACACCAGC ACCC ATTCACG CTC (SEQ ID NO: 17)(SEQ ID NO: 18) (SEQ ID NO: 19)

TABLE 4 Study results plasma liver liver/ Example dose exposure exposureplasma ratio # [mg/kg] 4 h 4 h 4 h  3/48 20 D C C  3/59 20 C C B  3/6420 C D D  3/73 10 D B C 5/3 20 D C B 8/8 10 C B B 10/1  10 D B C 10/2 10 D D B 11/11 20 D D D 11/12 20 D C C 11/13 20 A C A 11/16 20 C C B11/17 20 C D C 11/23 20 C C B 11/26 10 C C C 11/27 20 D C C 11/33 20 C CC 11/37 10 D C C 11/49 20 D C D 11/51 10 D C C 11/53 10 D C C 11/62 10 CC B 11/63 10 D C B 11/65 10 D C C 21/3  10 D C D 23/2  20 C A A 32/5  10D B B Fasn Srebp1c Scd1 suppression suppr. suppression Example comparedto compared to compared to # vehicle vehicle vehicle  3/48 20 D D D 3/59 20 C D C  3/64 20 B B D  3/73 10 A D D 5/3 20 D C C 8/8 10 D D D10/1  10 D D D 10/2  10 C C C 11/11 20 C D D 11/12 20 C D D 11/13 20 C DD 11/16 20 A B C 11/17 20 C D D 11/23 20 C D D 11/26 10 D D C 11/27 20 CA D 11/33 20 B D D 11/37 10 D D D 11/49 20 C C D 11/51 10 D D D 11/53 10D D D 11/62 10 D D D 11/63 10 C D C 11/65 10 D D D 21/3  10 C D D 23/2 20 C D D 32/5  10 C C C Ranges: plasma exposure: A: >1 μM, B: 300 nM to≤1 μM, C: 100 nM to <300 nM, D: <100 nM; liver exposure: A: <300 nM, B:300 nM to ≤1 μM, C: 1 μM to ≤10 μM, D: >10 μM; liver/plasma ratio: A:<5, B: 5 to ≤30, C: 30 to ≤100, D: >100; gene suppression: A: >0.9, B:0.6 to ≤0.9, C: 0.3 to ≤0.6, D: <0.3;

Triple oral dosing over two days (day one morning and evening, day twomorning) of compounds from the present invention in mice lead to a highliver exposure with a favourable liver-to-plasma ratio. Hepatic LXRtarget genes were effectively suppressed. These genes are involved inthe transcriptional regulation of hepatic de-novo lipogenesis (Wang etal., Nat. Rev. Mol. Cell Biol. 2015; 16:678). A suppression of thesegenes will reduce liver fat (liver triglycerides).

Comparative Examples

Example 3/32 FRETβ 551 nM (−98%) LBD-M2H Gal4α 106 nM (103%) LBD-M2HGal4β 13 nM (81%)

Comparative Example C3/29 FRETβ 4228 nM (−102%) FL-M2H Gal4α inactiveFL-M2H Gal4β inactive

Example 11/33 FRETβ 19 nM (−99%) FL-M2H Gal4α 1.3 nM (164%) FL-M2H Gal4β1.7 nM (130%)

Comparative Example C11/48 FRETβ 49 nM (−96%) FL-M2H Gal4α 62 nM (118%)FL-M2H Gal4β 32 nM (123%)

Comparative Example C11/39 FRETβ 104 nM (−91%) FL-M2H Gal4α 14 nM (117%)FL-M2H Gal4β 14 nM (140%)

The Comparative Examples illustrate that it can be advantageous, whenthe cyclic moiety in 3-position of the indole (or analog) has at leastone substituent in 1,2-orientation (ortho-substituent).

1. A compound represented by Formula (I)

a glycine conjugate, tauro conjugate, enantiomer, diastereomer,tautomer, N-oxide, solvate, prodrug and pharmaceutically acceptable saltthereof, wherein

is an annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms independentlyselected from N, O and S, wherein this cycle is unsubstituted orsubstituted with 1 to 4 substituents independently selected from thegroup consisting of halogen, CN, SF₅, NO₂, C₁₋₆-alkyl, oxo,C₀₋₆-alkylene-OR¹¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R¹¹, C₀₋₆-alkylene-NR¹¹S(O)₂R¹¹,C₀₋₆-alkylene-S(O)₂NR¹¹R¹², C₀₋₆-alkylene-NR¹¹S(O)₂NR¹¹R¹²,C₀₋₆-alkylene-CO₂R¹¹, O—C₁₋₆-alkylene-CO₂R¹¹, C₀₋₆-alkylene-O—COR¹¹,C₀₋₆-alkylene-CONR¹¹R¹², C₀₋₆-alkylene-NR¹¹—COR¹¹,C₀₋₆-alkylene-NR¹¹—CONR¹¹R¹², C₀₋₆-alkylene-O—CONR¹¹R¹²,C₀₋₆-alkylene-NR¹¹—CO₂R¹¹ and C₀₋₆-alkylene-NR¹¹R¹², wherein alkyl,alkylene, cycloalkyl and heterocycloalkyl is unsubstituted orsubstituted with 1 to 6 substituents independently selected fromhalogen, CN, oxo, hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl andO-halo-C₁₋₄-alkyl; and wherein optionally two adjacent substituents onthe aryl or heteroaryl moiety form a 5- to 8-membered partiallyunsaturated cycle optionally containing 1 to 3 heteroatoms independentlyselected from O, S or N, and wherein the new formed cycle isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halogen, CN, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3- to 6-memberedcycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-memberedheterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo,CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, O—C₁₋₄-alkyl andO-halo-C₁₋₄-alkyl;

is selected from the group consisting of 3- to 10-membered cycloalkyl,3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatomsindependently selected from N, O and S, 6- to 14-membered aryl and 5- to14-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl andheteroaryl are unsubstituted or substituted with 1 to 6 substituentsindependently selected from the group consisting of halogen, CN, SF₅,NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3- to6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-memberedheterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹, C₀₋₆-alkylene-NR²S(O)₂R²¹,C₀₋₆-alkylene-S(O)₂NR²¹R²², C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²²,C₀₋₆-alkylene-CO₂R²¹, O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹,C₀₋₆-alkylene-CONR²¹R²², C₀₋₆-alkylene-NR²¹—COR²¹,C₀₋₆-alkylene-NR²¹—CONR²¹R²², C₀₋₆-alkylene-O—CONR²¹R²²,C₀₋₆-alkylene-NR²¹—CO₂R²¹ and C₀₋₆-alkylene-NR²¹R²², wherein alkyl,alkylene, cycloalkyl and heterocycloalkyl is unsubstituted orsubstituted with 1 to 6 substituents independently selected fromhalogen, CN, oxo, hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl andO-halo-C₁₋₄-alkyl, and wherein optionally two adjacent substituents onthe aryl or heteroaryl moiety form a 5- to 8-membered partiallyunsaturated cycle optionally containing 1 to 3 heteroatoms independentlyselected from O, S or N, and wherein this additional cycle isunsubstituted or substituted with 1 to 4 substituents independentlyselected from halogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl andO-halo-C₁₋₄-alkyl, and wherein optionally two adjacent substituents onthe cycloalkyl or heterocycloalkyl moiety form a 5- to 6-memberedunsaturated cycle optionally containing 1 to 3 heteroatoms independentlyselected from O, S or N, wherein this additional cycle is unsubstitutedor substituted with 1 to 4 substituents independently selected fromhalogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H,C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

is selected from the group consisting of 6- or 10-membered aryl and 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms independentlyselected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl andheteroaryl are unsubstituted or substituted with 1 to 4 substituentsindependently selected from the group consisting of halogen, CN, SF₅,NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR³¹, C₀₋₆-alkylene-(3- to6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-memberedheterocycloalkyl), C₀₋₆-alkylene-(6-membered aryl), C₀₋₆-alkylene-(5- to6-membered heteroaryl), C₀₋₆-alkylene-S(O)_(n)R,C₀₋₆-alkylene-NR³¹S(O)₂R³¹, C₀₋₆-alkylene-S(O)₂NR³¹R³²,C₀₋₆-alkylene-NR³¹S(O)₂NR³¹R³², C₀₋₆-alkylene-CO₂R³¹,O—C₁₋₆-alkylene-CO₂R³¹, C₀₋₆-alkylene-O—COR³¹, C₀₋₆-alkylene-CONR³¹R³²,C₀₋₆-alkylene-NR³¹—COR³¹, C₀₋₆-alkylene-NR³¹—CONR³¹R³²,C₀₋₆-alkylene-O—CONR³¹R³², C₀₋₆-alkylene-NR³¹—CO₂R³¹ andC₀₋₆-alkylene-NR³¹R³², wherein alkyl, alkylene, cycloalkyl,heterocycloalkyl, aryl and heteroaryl is unsubstituted or substitutedwith 1 to 6 substituents independently selected from halogen, CN, oxo,hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; and whereinoptionally two adjacent substituents on the aryl or heteroaryl moietyform a 5- to 8-membered partially unsaturated cycle optionallycontaining 1 to 3 heteroatoms independently selected from O, S or N, andwherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl;

is selected from the group consisting of 3- to 10-membered cycloalkyl,3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatomsindependently selected from N, O and S, 6- to 14-membered aryl and 5- to14-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl andheteroaryl are unsubstituted or substituted with 1 to 6 substituentsindependently selected from the group consisting of halogen, CN, SF₅,NO₂, oxo, C₁₋₄-alkyl, C₀₋₆-alkylene-OR²¹, C₀₋₆-alkylene-(3- to6-membered cycloalkyl), C₀₋₆-alkylene-(3- to 6-memberedheterocycloalkyl), C₀₋₆-alkylene-S(O)_(n)R²¹, C₀₋₆-alkylene-NR²¹S(O)₂R²,C₀₋₆-alkylene-S(O)₂NR²¹R²², C₀₋₆-alkylene-NR²¹S(O)₂NR²¹R²²,C₀₋₆-alkylene-CR⁴¹(═N—OR⁴¹), C₀₋₆-alkylene-CO₂R²¹,O—C₁₋₆-alkylene-CO₂R²¹, C₀₋₆-alkylene-O—COR²¹, C₀₋₆-alkylene-CONR²¹R²²,C₀₋₆-alkylene-NR²¹—COR²¹, C₀₋₆-alkylene-NR²¹—CONR²¹R²²,C₀₋₆-alkylene-O—CONR²¹R²², C₀₋₆-alkylene-NR²¹—CO₂R²¹ andC₀₋₆-alkylene-NR²¹R²², wherein alkyl, alkylene, cycloalkyl andheterocycloalkyl is unsubstituted or substituted with 1 to 6substituents independently selected from halogen, CN, oxo, hydroxy,CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, CO—OC₁₋₄-alkyl,C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; andwherein optionally two adjacent substituents on the aryl or heteroarylmoiety form a 5- to 8-membered partially unsaturated cycle optionallycontaining 1 to 3 heteroatoms independently selected from O, S or N, andwherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; and whereinoptionally two adjacent substituents on the cycloalkyl orheterocycloalkyl moiety form a 5- to 6-membered unsaturated cycleoptionally containing 1 to 3 heteroatoms independently selected from O,S or N, wherein this additional cycle is unsubstituted or substitutedwith 1 to 4 substituents independently selected from halogen, CN, oxo,OH, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; wherein

has a substituent from above in 1,2-orientation regarding to theconnection towards

or has an annelated additional cycle in 1,2-orientation; L is selectedfrom the group consisting of a bond, C₁₋₆-alkylene, C₂₋₆-alkenylene,C2-alkinylene, 3- to 10-membered cycloalkylene, 3- to 10-memberedheterocycloalkylene containing 1 to 4 heteroatoms independently selectedfrom N, O and S, 6- or 10-membered arylene and 5- to 10-memberedheteroarylene containing 1 to 4 heteroatoms independently selected fromN, O and S, wherein alkylene, alkenylene, alkinylene, cycloalkylene,heterocycloalkylene, arylene and heteroarylene are unsubstituted orsubstituted with 1 to 6 substituents independently selected from thegroup consisting of halogen, CN, SF₅, NO₂, oxo, C₁₋₄-alkyl,C₀₋₆-alkylene-OR⁴¹, C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),C₀₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-NR⁴S(O)₂R⁴¹,C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR'S(O)₂NR⁴¹R⁴²,C₀₋₆-alkylene-CO₂R⁴¹, O—C₁₋₆-alkylene-CO₂R⁴¹, C₀₋₆-alkylene-O—COR⁴¹,C₀₋₆-alkylene-CONR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹—COR⁴¹,C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴², C₀₋₆-alkylene-O—CONR⁴¹R⁴²,C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹ and C₀₋₆-alkylene-NR⁴¹R⁴², wherein alkyl,alkylene, cycloalkyl and heterocycloalkyl is unsubstituted orsubstituted with 1 to 6 substituents independently selected fromhalogen, CN, oxo, hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl andO-halo-C₁₋₄-alkyl; and wherein optionally two adjacent substituents onthe arylene and heteroarylene moiety form a 5- to 8-membered partiallyunsaturated cycle optionally containing 1 to 3 heteroatoms independentlyselected from O, S or N, and wherein this additional cycle isunsubstituted or substituted with 1 to 4 substituents independentlyselected from halogen, CN, oxo, OH, CO₂H, CO₂—C₁₋₄-alkyl, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; R¹ is selected fromthe group consisting of H, halogen, CN, SF₅, NO₂, oxo, C₁₋₄-alkyl,C₀₋₆-alkylene-OR⁴, Y—C₀₋₆-alkylene-(3- to 6-membered cycloalkyl),Y—C₀₋₆-alkylene-(3- to 6-membered heterocycloalkyl),Y—C₀₋₆-alkylene-(6-membered aryl), Y—C₀₋₆-alkylene-(5- to 6-memberedheteroaryl), C₀₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵,X—C₁₋₆-alkylene-S(═O)(—R⁴¹)═N—R⁷⁵, C₀₋₆-alkylene-S(O)_(n)R⁴¹,X—C₁₋₆-alkylene-S(O)_(n)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹,X—C₁₋₆-alkylene-S(O)(═NR⁷¹)R⁴¹, C₀₋₆-alkylene-S(═NR⁷¹)₂R⁴¹,X—C₁₋₆-alkylene-S(═NR⁷¹)₂R⁴¹, C₀₋₆-alkylene-NR¹S(O)₂R¹,X—C₁₋₆-alkylene-NR⁴¹S(O)₂R⁴¹, C₀₋₆-alkylene-S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹S(O)₂NR⁴¹R⁴², C₀₋₆-alkylene-SO₃R⁴¹,X—C₁₋₆-alkylene-SO₃R⁴¹, C₀₋₆-alkylene-CO₂R⁴¹, X—C₁₋₆-alkylene-CO₂R⁴¹,C₀₋₆-alkylene-O—COR⁴¹, X—C₁₋₆-alkylene-O—COR⁴¹, C₀₋₆-alkylene-CONR⁴¹R⁴²,X—C₁₋₆-alkylene-CONR⁴¹R⁴², C₀₋₆-alkylene-CONR⁴¹OR⁴¹,X—C₀₋₆-alkylene-CONR⁴¹OR⁴¹, C₀₋₆-alkylene-CONR⁴¹SO₂R⁴¹,X—C₁₋₆-alkylene-CONR⁴¹SO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹—COR⁴¹,X—C₁₋₆—C₀₋₆-alkylene-NR⁴¹—COR, C₀₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-NR⁴¹—CONR⁴¹R⁴², C₀₋₆-alkylene-O—CONR⁴¹R⁴²,X—C₁₋₆-alkylene-O—CONR⁴¹R⁴², C₀₋₆-alkylene-NR⁴¹—CO₂R⁴¹,X—C₁₋₆-alkylene-NR⁴¹—CO₂R⁴¹, C₀₋₆-alkylene-NR⁴¹R⁴²,X—C₁₋₆-alkylene-N⁴¹R⁴², wherein alkyl, alkylene, cycloalkyl,heterocycloalkyl, aryl and heteroaryl is unsubstituted or substitutedwith 1 to 6 substituents independently selected from halogen, CN, oxo,hydroxy, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; and whereinoptionally two adjacent substituents on the aryl and heteroaryl moietyform a 5- to 8-membered partially unsaturated cycle optionallycontaining 1 to 3 heteroatoms independently selected from O, S or N, andwherein this additional cycle is unsubstituted or substituted with 1 to4 substituents independently selected from halogen, CN, oxo, OH, CO₂H,CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; R¹¹, R¹², R²¹, R²²,R³¹, R³², R⁴¹, R⁴², R⁵¹ are independently selected from H andC₁₋₄-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3substituents independently selected from halogen, CN, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-memberedcycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-memberedheterocycloalkyl), OH, oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H,CONH(CH₂)₂SO₃H, SO₃H, O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; or R¹¹ andR¹², R²¹ and R²², R³¹ and R³², R⁴¹ and R⁴², respectively, when takentogether with the nitrogen to which they are attached complete a 3- to6-membered ring containing carbon atoms and optionally containing 1 or 2heteroatoms independently selected from O, S or N; and wherein the newformed cycle is unsubstituted or substituted with 1 to 3 substituentsindependently selected from halogen, CN, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3-to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl),OH, oxo, CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H,O—C₁₋₄-alkyl and O-halo-C₁₋₄-alkyl; R⁷¹ is independently selected fromH, CN; NO₂, C₁₋₄-alkyl and C(O)—OC₁₋₄-alkyl, wherein alkyl isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halogen, CN, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, 3- to 6-memberedcycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-memberedheterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo,CO₂H, CO₂—C₁₋₄-alkyl, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H, O—C₁₋₄-alkyland O-halo-C₁₋₄-alkyl; R⁷⁵ is independently selected from C₁₋₄-alkyl, 3-to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6-memberedaryl and 5- to 6-membered heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl is unsubstituted or substitutedwith 1 to 3 substituents independently selected from halogen, CN, Me,Et, CHF₂, CF₃, OH, oxo, CO₂H, CONHCH₂CO₂H, CONH(CH₂)₂SO₃H, SO₃H, OMe,OEt, OCHF₂, and OCF₃; X is independently selected from O, NR⁵¹,S(O)_(n), S(═NR⁷¹), S(O═NR⁷¹) and S(═NR⁷¹)₂; Y is independently selectedfrom a bond, O, NR, S(O)_(n), S(═NR⁷¹), S(O═NR⁷¹) and S(═NR⁷¹)₂; n isindependently selected from 0 to 2; and with the proviso, that thefollowing structures are excluded:


2. The compound according to claim 1 wherein

is selected from

wherein

is unsubstituted or substituted with 1 to 3 substituents independentlyselected from the group consisting of F, Cl, Br, CN, OH, oxo,C1-4-alkyl, halo-C1-4-alkyl, O—C1-4-alkyl, O-halo-C1-4-alkyl, NH2,NHC1-4-alkyl, N(C1-4-alkyl)2, SO2-C1-4-alkyl and SO2-halo-C1-4-alkyl. 3.The compound according to claim 1 wherein

is selected from the group consisting of phenyl, naphthyl, pyridyl,pyrimidinyl, thiophenyl, thiazolyl, cyclopentyl, cyclohexyl,bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl,pentacyclo[4.2.0.0^(2,5).0^(3,8).0^(4,7)]octyl and piperidinyl, whereinthe cycle is unsubstituted or substituted with 1 to 3 substituentsindependently selected from the group consisting of F, Cl, Br, CN, OH,oxo, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl, O-halo-C₁₋₄-alkyl,C₁₋₄-alkyl-OH and halo-C₁₋₄-alkyl-OH; and wherein optionally twoadjacent substituents on the phenyl ring form together a —(CH₂)₃—,—(CH₂)₄—, —OCF₂O— and —OCH₂O— group.
 4. The compound according to claim1 wherein

is selected from phenyl, pyridyl and thiophenyl; wherein phenyl, pyridyland thiophenyl is unsubstituted or substituted with 1 to 3 substituentsindependently selected from the group consisting of F, Cl, CN, OH, oxo,C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl and O-halo-C₁₋₄-al 1 andwherein residue -L-R is linked in 1,3-orientation regarding theconnection towards

and L is not a bond.
 5. The compound according to claim 1 wherein -L-R¹is selected from

wherein the cycle is unsubstituted or further substituted with 1 to 4substituents independently selected from the group consisting of F, Cl,Br, CN, OH, oxo, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, O—C₁₋₄-alkyl,O-halo-C₁₋₄-alkyl, C₁₋₄-alkyl-OH, halo-C₁₋₄-alkyl-OH, SO₂—C₁₋₄-alkyl andSO₂-halo-C₁₋₄-alkyl; and wherein optionally two adjacent substituents onthe phenyl ring form together a —(CH₂)₃—, —(CH₂)₄—, —OCF₂O— and —OCH₂O—group.
 6. The compound according to claim 5 wherein R¹ is selected fromCO₂H, tetrazole, CH₂CO₂H, OCH₂CO₂H, SO₂CH₂CO₂H, CHMeCO₂H, CMe₂CO₂H,C(OH)MeCO₂H, CONHSO₂Me and CONH(OH); and optionally the glycine andtauro conjugate thereof.
 7. The compound according to claim 1 wherein-L-R¹ is selected from

and optionally the glycine and tauro conjugate thereof.
 8. The compoundaccording to claim 1 wherein

is selected from the group consisting

wherein R² is selected from Me, F, Cl, CN, Me, CHO, CHF₂, CF₃, SO₂Me,

and wherein

is optionally further substituted with 1 to 2 substituents selected fromthe group consisting F, Cl, CN, Me, OMe, CHO, CHF₂ and CF₃.
 9. Thecompound according to claim 1 wherein

is selected from the group consisting of


10. The compound according to claim 1 wherein Formula (I) contains asubstituent selected from the group consisting of CO₂H, tetrazole,CONHSO₂Me and CONH(OH); and optionally the glycine and tauro conjugatethereof.
 11. The compound according to claim 1 selected from

or a glycine conjugate or tauro conjugate thereof, and an enantiomer,diastereomer, tautomer, N-oxide, solvate, prodrug and pharmaceuticallyacceptable salt thereof.
 12. A medicament comprising a compoundaccording to claim
 1. 13. A method for the prophylaxis and/or treatmentof diseases amenable for treatment with LXR modulators, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound according to claim
 1. 14. The method according toclaim 13 wherein the disease is selected from non-alcoholic fatty liverdisease, non-alcoholic steatohepatitis, liver inflammation, liverfibrosis, obesity, insulin resistance, type II diabetes, familialhypercholesterolemia, hypercholesterolemia in nephrotic syndrome,metabolic syndrome, cardiac steatosis, cancer, viral myocarditis,hepatitis C virus infection or its complications, and unwantedside-effects of long-term glucocorticoid treatment in diseases such asrheumatoid arthritis, inflammatory bowel disease and asthma.
 15. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier or excipient.